Enzymatic encoding methods for efficient synthesis of large libraries

ABSTRACT

Disclosed is a method for obtaining a bifunctional complex comprising a molecule linked to a single stranded identifier oligonucleotide, wherein a nascent bifunctional complex comprising a chemical reaction site and a priming site for enzymatic addition of a tag is a) reacted at the chemical reaction site with one or more reactants, and b) reacted enzymatically at the priming site with one or more tag(s) identifying the reactant(s).

This application is a non-provisional of U.S. provisional applicationSer. No. 60/741,490 filed on Dec. 2, 2005, which is hereby incorporatedby reference in its entirety. All patent and non-patent references citedin U.S. provisional application Ser. No. 60/741,490, or in the presentapplication, are also hereby incorporated by reference in theirentirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to bifunctional complexes and methods forsynthesising such complexes, as well as to methods for split-and-mixsynthesis of different molecules each linked to a single strandedidentifier oligonucleotide comprising a plurality of tags identifyingthe molecule and/or the chemical entities having participated in thesynthesis of the molecule. The invention also relates to a method forgenerating a library of different bifunctional complexes and methods forselecting molecules and/or identifying molecules having a desirableproperty, such as affinity for a target compound.

BACKGROUND OF THE INVENTION

Synthesis methods known as split-and-mix, or split-and-recombine, areknown and have been used for the synthesis of different molecules.Split-and-mix methods for synthesising polypeptides and otherbiochemical polymers have been disclosed e.g. in U.S. Pat. No. 5,723,598directed to the generation of a library of bifunctional complexescomprising a polypeptide and an identifier oligonucleotide comprisingtags in the form of a sequence of nucleotides identifying the aminoacids which participated in the formation of the polypeptide. Themethods are directed to chemical linkage of tags and do not discloseenzymatic linkage, such as ligation, of the nucleotide tags making upthe identifier oligonucleotide.

WO 00/23458 discloses a split-and-mix method in which nucleic acid tagsare involved in both molecule synthesis and molecule identification. WO2004/039825 and WO 2005/058479 disclose split-and-mix methods whereintags in the form of identifier oligonucleotides are linkedenzymatically. The prior art methods do not disclose ligation of adouble-stranded oligonucleotide substrate comprising a plurality of tagsand complementary anti-tags at least partly hybridised to each other,wherein said ligation results in the formation of an identifieroligonucleotide comprising a plurality of consecutive nucleotides in theform of covalently linked tags, whereas the anti-tags of thedouble-stranded oligonucleotide substrate are not affected by the actionof the ligase, i.e. no anti-tags become covalently linked as a result ofthe enzymatic ligation of the tag part of the double-strandedoligonucleotide substrate.

Reference is also made to WO2006/053571 disclosing methods for moleculesynthesis.

SUMMARY OF THE INVENTION

There is a need for improved methods for split-and-mix synthesis oflibraries of small molecules for e.g. pharmaceutical and other purposes.The small molecules can initially be synthesised as part of abifunctional complex further comprising an identifier oligonucleotideidentifying the reactants which have participated in the synthesis ofthe small molecule.

The methods of the present invention employs a ligation step wherein thesubstrate for the ligase is in a double stranded form and wherein thesubstrate comprises a plurality of tags and at least one or moreanti-tags wherein tags and anti-tag(s) is/are at least partly hybridisedto each other. The tags are covalently linked as a result of the actionof an enzyme comprising a ligase activity on the double strandedsubstrate, but no anti-tags are covalently linked as a result of saidligase action.

The method facilitates separation of ligated tags and discrete,non-ligated anti-tags because of the size and molecular weightdifference between (i) the afore-mentioned single stranded identifieroligonucleotide comprising a plurality of covalently linked tags and(ii) discrete, non-ligated anti-tags. The identifier oligonucleotidecomprising the ligated tags will typically have a length at least about3 times the length of the individual anti-tags.

In one embodiment, the tags comprise a 5′ phosphate, or a variantligatable reactive group, whereas anti-tags do not. Therefore, thegrowing bifunctional complex will comprise a covalently linked“top”-strand to which a number, such as one or more, of shorter andnon-ligated anti-tag(s) is/are hybridised/annealed. This enables removalof anti-tag(s), e.g. after all tag additions have been performed(FIG. 1) or after each tag addition has been performed (FIG. 6).

Removal of anti-tags generally increases fidelity and allows extensionafter purification of the single-stranded oligonucleotide identifiercomprising a plurality of ligated tags. Said extension makes possiblethe use of selection-specific sequences, which improves robustnesstowards contamination, which is a well-known phenomena when e.g. PCRamplifications are performed. Also, diversification-sequences can beused which diversifies otherwise un-distinguishable tag combinations.This makes it possible to identify tag combination sequences which mayarise during PCR from a single tag combination. It is advantageous toidentify such sequences as they may otherwise be interpreted as arisingfrom several molecular entities containing the same tag combination,thus indicating that the specific tag combination corresponds to a smallmolecule with relatively high ability to be retained during subsequentselection procedures.

Also, because of the design of the tags, cross-hybridization betweensingle stranded tags can be reduced or essentially eliminated. Thisgreatly improves the purification process of the bifunctional complexescomprising single stranded identifier oligonucleotides following thesynthesis reactions. One problem associated with purification ofbifunctional complexes comprising double stranded identifieroligonucleotides is that such identifiers are prone to illegitimatehybridization when renaturing conditions are resumed following apurification process under denaturing conditions.

In order to achieve a minimum degree of cross-hybridization between tagsin an identifier oligonucleotide, the tags can be designed using acomputer algorithm to maximize or optimize the number of mismatchesbetween any oligo pair, e.g. resulting in a minimum of seven mismatchesbetween any two tag tags. This maximizes or optimize fidelity ofhybridization and enables use of sorting methods, such as the onesdisclosed e.g. in WO 00/23458 (Harbury). Moreover, it increasesrobustness of decoding by sequencing, e.g. the tag information can bedecoded even if sequencing errors occur.

It is also possible to perform a quenching reaction with the reactantsand tags. After reactant reactions resulting in the synthesis of themolecule, excess reactants are rendered un-reactive, e.g., by adding aquencher in the form e.g. of a reactant which reacts with excessreactants, e.g. by raising pH, etc, or by removal of a reactant which iscritical for the reaction, etc. This can be done e.g. prior to, after orin parallel with deprotection of reacted reactants.

The same principle can be applied to the tags. Unreacted tags can berendered unreactive at one or more tag reaction site(s), e.g., bydephosphorylation of tags containing 5′ phosphates. Advantagesassociated with these steps include higher fidelity and the possibleomission of purification steps between reaction cycles.

The same principle can also be applied to the chemical reaction site onthe growing complexes.

In one embodiment of the present invention there is provided a methodfor the synthesis of a bifunctional complex comprising a molecule and asingle stranded oligonucleotide identifier attached to the molecule,said method comprising the steps of

-   -   i) providing a display oligonucleotide attached to        -   a) one or more chemical reaction site(s) comprising one or            more reactive groups and        -   b) one or more priming site(s) for enzymatic addition of a            tag,    -   ii) providing a first reactant comprising one or more chemical        entities and one or more reactive groups capable of reacting        with        -   c) the one or more chemical reaction site(s) of the display            oligonucleotide, and/or        -   d) one or more reactive groups of at least a first further            reactant comprising one or more chemical entities, wherein            said first further reactant is provided simultaneously or            sequentially in any order with the first reactant,    -   iii) providing a first oligonucleotide tag capable of        hybridising to part of a first oligonucleotide anti-tag, wherein        the first oligonucleotide tag identifies the first reactant and,        optionally, the further first reactant,    -   iv) providing a first oligonucleotide anti-tag capable of        hybridising to at least part of the first oligonucleotide tag        provided in step iii) and to at least part of the display        oligonucleotide provided in step i),    -   v) reacting the first reactant provided in step ii) with c) the        one or more chemical reaction site(s) of the display        oligonucleotide and/or with d) the one or more reactive groups        of the first further reactant comprising one or more chemical        entities,        -   wherein the reaction of complementary reactive groups result            in the formation of a covalent bond, and        -   wherein one or more reactive group reactions of step v)            result in the formation of one or more covalent bond(s)            between the one or more chemical reaction site(s) of the            display oligo and at least one chemical entity of at least            one reactant selected from the group consisting of the first            reactant and the further first reactant,    -   vi) hybridising the anti-tag to the display oligonucleotide and        to the first oligonucleotide tag,        -   wherein method steps v) and vi) are simultaneous or            sequential in any order,    -   vii) enzymatically ligating the display oligonucleotide and the        first oligonucleotide tag,    -   viii) providing a second reactant comprising one or more        chemical entities and one or more reactive groups capable of        reacting with        -   c) the one or more chemical reaction site(s) of the display            oligonucleotide, and/or        -   d) one or more reactive groups of one or more reactant(s)            having reacted in a previous synthesis round, and/or        -   e) one or more reactive groups of a second further reactant            comprising one or more chemical entities, wherein said            second further reactant is provided simultaneously or            sequentially in any order with the second reactant,    -   ix) providing a second oligonucleotide tag capable of        hybridising to part of a second oligonucleotide anti-tag,        wherein the second oligonucleotide tag identifies the second        reactant and, optionally, the further second reactant,    -   x) providing a second oligonucleotide anti-tag capable of        hybridising to part of the first oligonucleotide tag provided in        step iii) and to part of the second oligonucleotide tag provided        in step ix),    -   xi) reacting the second reactant provided in step viii) with c)        the one or more chemical reaction site(s) of the display        oligonucleotide and/or d) one or more reactive groups of one or        more reactant(s) having reacted in a previous synthesis round        and/or e) one or more reactive groups of a further second        reactant comprising one or more chemical entities,        -   wherein the reaction of complementary reactive groups result            in the formation of a covalent bond, and        -   wherein one or more reactive group reactions of step xi)            result in        -   f) the formation of one or more covalent bond(s) between the            one or more chemical reaction site(s) and at least one            chemical entity of at least one reactant selected from the            group consisting of the second reactant and the further            second reactant, and/or        -   g) the formation of one or more covalent bond(s) between a            reactant having reacted in a previous synthesis round and at            least one chemical entity of at least one reactant selected            from the group consisting of the second reactant and the            further second reactant,    -   xii) hybridising the anti-tag to the first oligonucleotide tag        and the second oligonucleotide tag,        -   wherein method steps xi) and xii) are simultaneous or            sequential in any order,    -   xiii) enzymatically ligating the first and second        oligonucleotide tags in the absence of ligation the first and        second anti-tag oligonucleotides, and optionally    -   xiv) displacing unligated anti-tags from the bifunctional        complex comprising a molecule and a single stranded        oligonucleotide identifier comprising tags identifying the        reactants which participated in the synthesis of the molecule.

It is clear from the above that the claimed method for synthesis of abifunctional molecule covers a number of alternative embodiments—as wellas combinations of a number of such alternative embodiments. The belowoverview aim to specifically disclose a number of alternativeembodiments and combinations thereof.

In step ia) there is provided a display oligonucleotide. In oneembodiment the display oligonucleotide has one chemical reaction sitecomprising one or more reactive groups. A chemical reaction sitecomprising more than one reactive group can be used for the synthesis ofboth linear molecules, branched molecules, cyclical molecules and thechemical reaction site can be in the form of a scaffold for thesynthesis of small, scaffolded molecules.

In another embodiment, the display oligonucleotide has more than onechemical reaction site each comprising one or more reactive groups.

For each of the above alternatives the display oligonucleotide can haveone or more priming sites. Accordingly, as far as step i) is concerned,the following alternatives are provided:

A display oligonucleotide comprising one chemical reaction site and onepriming site;A display oligonucleotide comprising more than one chemical reactionsite and one priming site;A display oligonucleotide comprising one chemical reaction site and morethan one priming site; andA display oligonucleotide comprising more than one chemical reactionsite and more than one priming site.

Each of the above-mentioned sites can have one or more reactive groups.When more sites are provided, there is also provided an embodimentwherein one site has one reactive group whereas the remaining sites havemore than one reactive group.

In step ii) there is provided a first reactant comprising one or morechemical entities, wherein each entity has one or more reactive groups.Accordingly, as far as step ii) is concerned, the following alternativesare provided:

A first reactant comprising one chemical entity having one reactivegroup;A first reactant comprising more than one chemical entity each havingone reactive group;A first reactant comprising one chemical entity each having more thanone reactive group; andA first reactant comprising more than one chemical entity each havingmore than one reactive group.

In one embodiment, a display oligonucleotide selected from the groupconsisting of a display oligonucleotide comprising one chemical reactionsite and one priming site; a display oligonucleotide comprising morethan one chemical reaction site and one priming site; a displayoligonucleotide comprising one chemical reaction site and more than onepriming site; and a display oligonucleotide comprising more than onechemical reaction site and more than one priming site, is reacted with afirst reactant selected from the group consisting of a first reactantcomprising one chemical entity having one reactive group; a firstreactant comprising more than one chemical entity each having onereactive group; a first reactant comprising one chemical entity eachhaving more than one reactive group; and a first reactant comprisingmore than one chemical entity each having more than one reactive group.

Step ii) also allows a reaction to occur between a first reactant and afurther first reactant, wherein the reaction product reacts,simultaneously or sequentially in any order, with a chemical reactionsite of a display molecule. Accordingly, there is also provided in stepii):

A first further reactant comprising one chemical entity having onereactive group;A first further reactant comprising more than one chemical entity eachhaving one reactive group;A first further reactant comprising one chemical entity having more thanone reactive group; andA first further reactant comprising more than one chemical entity eachhaving more than one reactive group.

Consequently, there is provided in one embodiment a reaction between afirst reactant selected from the group consisting of a first reactantcomprising one chemical entity having one reactive group; a firstreactant comprising more than one chemical entity each having onereactive group; a first reactant comprising one chemical entity havingmore than one reactive group; and a first reactant comprising more thanone chemical entity each having more than one reactive group, and afirst further reactant selected from the group consisting of a firstfurther reactant comprising one chemical entity having one reactivegroup; a first further reactant comprising more than one chemical entityeach having one reactive group; a first further reactant comprising onechemical entity having more than one reactive group; and a first furtherreactant comprising more than one chemical entity each having more thanone reactive group.

In step viii) there is provided a second reactant comprising one or morechemical entities, wherein each entity has one or more reactive groups.Accordingly, as far as step ii) is concerned, the following alternativesare provided:

A second reactant comprising one chemical entity having one reactivegroup;A second reactant comprising more than one chemical entity each havingone reactive group;A second reactant comprising one chemical entity each having more thanone reactive group; andA second reactant comprising more than one chemical entity each havingmore than one reactive group.

In one embodiment, a display oligonucleotide selected from the groupconsisting of a display oligonucleotide comprising one chemical reactionsite and one priming site; a display oligonucleotide comprising morethan one chemical reaction site and one priming site; a displayoligonucleotide comprising one chemical reaction site and more than onepriming site; and a display oligonucleotide comprising more than onechemical reaction site and more than one priming site, wherein one ormore chemical reaction sites have reacted with one or more reactants ina first or previous reaction round, is reacted with a second reactantselected from the group consisting of a second reactant comprising onechemical entity having one reactive group; a second reactant comprisingmore than one chemical entity each having one reactive group; a secondreactant comprising one chemical entity each having more than onereactive group; and a second reactant comprising more than one chemicalentity each having more than one reactive group.

Step viii) also allows a reaction to occur between a second reactant anda further second reactant, wherein the reaction product reacts,simultaneously or sequentially in any order, with a chemical reactionsite of a display molecule, or a reactive group of a reactant havingreacted with one or more chemical reaction sites of the displayoligonucleotide in a previous reaction round. Accordingly, there is alsoprovided in step viii):

A second further reactant comprising one chemical entity having onereactive group;A second further reactant comprising more than one chemical entity eachhaving one reactive group;A second further reactant comprising one chemical entity having morethan one reactive group; andA second further reactant comprising more than one chemical entity eachhaving more than one reactive group.

Consequently, there is provided in one embodiment a reaction between asecond reactant selected from the group consisting of a second reactantcomprising one chemical entity having one reactive group; a secondreactant comprising more than one chemical entity each having onereactive group; a second reactant comprising one chemical entity havingmore than one reactive group; and a second reactant comprising more thanone chemical entity each having more than one reactive group, and asecond further reactant selected from the group consisting of a secondfurther reactant comprising one chemical entity having one reactivegroup; a second further reactant comprising more than one chemicalentity each having one reactive group; a second further reactantcomprising one chemical entity having more than one reactive group; anda second further reactant comprising more than one chemical entity eachhaving more than one reactive group.

In one embodiment, a reactant having reacted in a previous reactionround with one or more chemical reaction sites of a displayoligonucleotide, or a reactant having previously reacted with a reactanthaving reacted with said one or more chemical reaction sites, is to beregarded as a chemical reaction site capable of reacting with one ormore reactants provided in a subsequent reaction round.

When a library of different bifunctional complexes are synthesised bysplit-and-mix methods according to the present invention, thecomposition of nascent bifunctional complexes obtained in step vii) issplit (divided) into a plurality of different compartments. In eachdifferent compartment, a different second reactant is provided, c.f.step viii) above. Also, in each different compartment a secondoligonucleotide tag is added, c.f. step ix) above, said secondoligonucleotide tag identifying in each different compartment the secondreactant, and optionally also the further second reactant, provided inthe same compartment as the second oligonucleotide tag.

In each different compartment a suitable anti-tag is provided, c.f. stepx) above, and hybridised to at least partly complementary tags, c.f.step xii) above.

The reaction cited in step xi) herein above takes place in eachdifferent compartment, resulting in the synthesis in each differentcompartment of different nascent bifunctional complexes comprising theresult (reaction product in the form of a molecule or moleculeprecursor) of a reaction involving the first and second reactants, andoptionally also the further first reactant and/or the further secondreactant, wherein said reaction product of the nascent bifunctionalproduct is linked to a corresponding identifier oligonucleotidecomprising the first and second oligonucleotide tags, c.f. step xiv). Atthe end of each synthesis round, the generated, nascent or finalbifunctional complex is optionally separated from unligated anti-tags.However, this separation step can also be carried out only once, afterthe final synthesis round.

The different bifunctional complexes from a given round of synthesis arecombined and split in order to initiate a new synthesis round, c.f.steps viii) to xii) above, which are repeated for a different reactantand optionally a different further reactant.

Taking the above library synthesis steps into consideration, the presentinvention is in one embodiment directed to a method for the synthesis ofa plurality of different bifunctional complexes, said method comprisingthe steps of

-   -   i) providing a plurality of display oligonucleotides each        attached to        -   a) one or more chemical reaction site(s) comprising one or            more reactive groups and        -   b) one or more priming site(s) for enzymatic addition of a            tag,    -   ii) providing a plurality of first reactants each comprising one        or more chemical entities and one or more reactive groups, each        first reactant being capable of reacting with        -   c) the one or more chemical reaction site(s) of the display            oligonucleotide, and/or        -   d) one or more reactive groups of a first further reactant            comprising one or more chemical entities, wherein said first            further reactant is provided simultaneously or sequentially            in any order with the first reactant,    -   iii) providing a plurality of first oligonucleotide tags each        capable of hybridising to part of a first oligonucleotide        anti-tag, wherein each first oligonucleotide tag identifies a        first reactant and, optionally, a further first reactant,    -   iv) providing a plurality of first oligonucleotide anti-tags        each capable of hybridising to at least part of a first        oligonucleotide tag provided in step iii) and to at least part        of a display oligonucleotide provided in step i),    -   v) reacting each of the first reactants provided in step ii)        with c) the one or more chemical reaction site(s) of the display        oligonucleotides and/or with d) the one or more reactive groups        of a first further reactant comprising one or more chemical        entities,        -   wherein the reaction of complementary reactive groups result            in the formation of a covalent bond, and        -   wherein one or more reactive group reactions of step v)            result in the formation of one or more covalent bond(s)            between the one or more chemical reaction site(s) of the            display oligonucleotides and at least one chemical entity of            at least one reactant selected from the group consisting of            a first reactant and a further first reactant,    -   vi) hybridising anti-tags to display oligonucleotides and to        first oligonucleotide tags,        -   wherein method steps v) and vi) are simultaneous or            sequential in any order,    -   vii) enzymatically ligating display oligonucleotides and first        oligonucleotide tags,    -   viii) dividing the plurality of nascent bifunctional complexes        obtained in step vii) into a plurality of different        compartments,    -   ix) providing in each different compartment a plurality of        different second reactants each comprising one or more chemical        entities and one or more reactive groups capable of reacting        with        -   c) the one or more chemical reaction site(s) of each of the            display oligonucleotides, and/or        -   d) one or more reactive groups of one or more reactant(s)            having reacted in a previous synthesis round, and/or        -   e) one or more reactive groups of a second further reactant            comprising one or more chemical entities, wherein said            second further reactants are provided simultaneously or            sequentially in any order with the second reactants,    -   x) providing in each different compartment a plurality of second        oligonucleotide tags each capable of hybridising to part of a        second oligonucleotide anti-tag, wherein different second        oligonucleotide tags are provided in each different compartment,        and wherein each different second oligonucleotide identifies a        different second reactant and, optionally, a further second        reactant which may be the same or a different further second        reactant in each different compartment,    -   xi) providing in each different compartment a plurality of        second oligonucleotide anti-tags capable of hybridising to part        of a first oligonucleotide tag provided in step iii) and to part        of a second oligonucleotide tag provided in step x),    -   xii) reacting in each different compartment each of the        different second reactants provided in step ix) with c) the one        or more chemical reaction site(s) of a display oligonucleotide        and/or d) one or more reactive groups of one or more reactant(s)        having reacted in a previous synthesis round and/or e) one or        more reactive groups of a further second reactant comprising one        or more chemical entities,        -   wherein said one or more reactions result in the formation            of different bifunctional complexes in each different            compartment,        -   wherein the reaction of complementary reactive groups result            in the formation of a covalent bond, and        -   wherein one or more reactive group reactions of step xii)            result in        -   f) the formation of one or more covalent bond(s) between the            one or more chemical reaction site(s) and at least one            chemical entity of at least one reactant selected from the            group consisting of second reactants and further second            reactants, and/or        -   g) the formation of one or more covalent bond(s) between a            reactant having reacted in a previous synthesis round and at            least one chemical entity of at least one reactant selected            from the group consisting of second reactants and further            second reactants,    -   xiii) hybridising anti-tags to first oligonucleotide tags and        second oligonucleotide tags in each different compartment,        -   wherein method steps xii) and xiii) are simultaneous or            sequential in any order,    -   xiv) enzymatically ligating in each different compartment first        and second oligonucleotide tags in the absence of ligation first        and second anti-tag oligonucleotides, and optionally    -   xv) displacing in each compartment unligated anti-tags from        bifunctional complexes comprising a molecule and a single        stranded oligonucleotide identifier comprising tags identifying        the one or more reactants which participated in the synthesis of        the molecule.

The above steps viii) to xv) can be repeated once or more than onceusing different reactants and tags identifying said different reactants.Prior to the repetition of the afore-mentioned steps the synthesisedbifunctional complexes are combined and split into different reactioncompartments.

As will be clear from the above, the present invention in one embodimentallows for efficient, enzymatic ligation of a plurality ofsingle-stranded tags making up one strand only of an at least partlydouble stranded, identifier oligonucleotide hybridisation complex (atleast at the time of ligation), wherein anti-tags at least partlyhybridised to the tags are not ligated and can easily be disposed ofafter each synthesis round (FIG. 6) or after molecule synthesis havebeen completed (FIG. 1).

None of the prior art methods disclose the formation of a doublestranded, identifier oligonucleotide precursor comprising complementarytags and anti-tags which are at least partly hybridised to each other,but not covalently linked. That is, prior to ligation, a tag caninitially be hybridised to an anti-tag of the complementary strand ofthe double stranded, identifier oligonucleotide precursor, but notcovalently linked to either such an anti-tag, or to another tag formingpart of the same strand of the double stranded, identifieroligonucleotide precursor.

Likewise, an anti-tag can initially be hybridised to a tag of thecomplementary strand of the double stranded, identifier oligonucleotideprecursor, but not covalently linked to either such a tag, or to anotheranti-tag forming part of the same strand of the double stranded,identifier oligonucleotide precursor.

In a further aspect of the invention there is provided a method forobtaining a bifunctional complex comprising a molecule and an identifieroligonucleotide. Initially, a nascent bifunctional complex comprisingone or more chemical reaction site(s) and one or more priming site(s)for enzymatic addition of a tag is reacted a) at the chemical reactionsite with one or more reactant(s) in the form of chemical entities andb) reacted at the priming site with one or more identifieroligonucleotide tag(s) identifying the reactant(s) which have reacted—orare going to react—with each other and/or with the chemical reactionsite, wherein tag ligation results in the formation only of a singlestranded identifier oligonucleotide comprising a plurality of tags,whereas no anti-tag at least partly hybridised the one or more tags areligated to a neighbouring anti-tag.

There is also provided a bifunctional complex as disclosed herein. Inone aspect, the bifunctional complex is an intermediate bifunctionalcomplex comprising a molecule precursor and a single stranded identifieroligonucleotide identifying the molecule precursor, wherein the singlestranded identifier comprises a plurality of covalently linked tagswhich are at least partly hybridised to one or more correspondinganti-tag(s), wherein, when more anti-tags are present, said anti-tagsare not covalently linked to each other.

In another aspect there is provided a bifunctional complex comprising amolecule and a single stranded identifier oligonucleotide identifyingthe molecule, wherein the single stranded identifier comprises aplurality of covalently linked tags which are at least partly hybridisedto one or more corresponding anti-tag(s), wherein, when more anti-tagsare present, said anti-tags are not covalently linked.

In a still further aspect there is provided a bifunctional complexcomprising a molecule and a single stranded identifier oligonucleotideidentifying the molecule, wherein the single stranded identifiercomprises a plurality of covalently linked tags.

There is also provided a method for synthesising a library of differentbifunctional complexes. The lack of a covalent link between a reactantand a tag means that a library can be produced by a split-and-mixstrategy. In a first step a display oligonucleotide or a nascentbifunctional complex is dispensed in separate compartments andsubsequently exposed to a different reactant in each or at least themajority of the compartments. The reactant reacts in each compartmentwith at least one reactive group of the chemical reaction site and a tagidentifying the reactant is added by enzymatic action at the primingsite. In one embodiment of the invention, the tag is added to thepriming site by enzymatic ligation.

There is also provided a method for partitioning a library orcomposition of different bifunctional complexes, said partitioningresulting in the selection of bifunctional complexes comprisingmolecules having one or more desirable characteristics. The partitioningof bifunctional complexes can occur as a result of the differentialaffinity of the molecule(s) of different bifunctional complexes for thesame or different targets, such as the targets disclosed herein.Alternatively, and/or in combination with the above, partitioning ofbifunctional complexes can occur based on tag features, such as e.g. tagnucleotide sequences and/or physical properties capable ofdistinguishing different tags and/or identifier oligonucleotides fromeach other.

Whereas an initially generated library is often termed a “naïvelibrary”, the library obtained after partitioning is often termed an“intelligent” or “enriched” library. The partitioning can be carried outonce or more than once using the same or different partitioningparameters, such as binding affinity to a target compound underpredetermined assaying conditions.

In a further aspect there is provided a pharmaceutical compositioncomprising the molecule, or a variant of the molecule, of thebifunctional complex—wherein preferably the molecule is not linked tothe identifier oligonucleotide of the bifunctional complex. The terms“molecule”, “compound”, “chemical compound”, “reaction product”,“bioactive agent” and “bioactive species” are used interchangably hereinwhen referring to a product obtained by the methods of the presentinvention, or a variant of such a product obtained e.g. when a “leadcompound” or “drug lead” is being optimised for pharmaceutical uses. A“bioactive agent” or a “bioactive species” is typically a molecule whichexerts a biologically relevant activity, such as e.g. a biologicallyrelevant binding affinity for a target compound.

There is also provided the use of a bifunctional complex according tothe invention in the manufacture of a medicament for the treatment of aclinical indication in an individual in need thereof.

DEFINITIONS

α-peptide: Peptide comprising or essentially consisting of at least two□-amino acids linked to one another by a linker including a peptidebond.

Amino acid: Entity comprising an amino terminal part (NH₂) and a carboxyterminal part (COOH) separated by a central part comprising a carbonatom, or a chain of carbon atoms, comprising at least one side chain orfunctional group. NH₂ refers to the amino group present at the aminoterminal end of an amino acid or peptide, and COOH refers to the carboxygroup present at the carboxy terminal end of an amino acid or peptide.The generic term amino acid comprises both natural and non-natural aminoacids. Natural amino acids of standard nomenclature as listed in J.Biol. Chem., 243:3552-59 (1969) and adopted in 37 C.F.R., section1.822(b) (2) belong to the group of amino acids listed herein below.Non-natural amino acids are those not listed in the below table.Examples of non-natural amino acids are those listed e.g. in 37 C.F.R.section 1.822(b) (4), all of which are incorporated herein by reference.Further examples of non-natural amino acids are listed herein below.Amino acid residues described herein can be in the “D” or “L” isomericform.

Symbols 1-Letter 3-Letter Amino acid Y Tyr tyrosine G Gly glycine F Phephenylalanine M Met methionine A Ala alanine S Ser serine I Ileisoleucine L Leu leucine T Thr threonine V Val valine P Pro proline KLys lysine H His histidine Q Gln glutamine E Glu glutamic acid W Trptryptophan R Arg arginine D Asp aspartic acid N Asn asparagine C Cyscysteine

Amino acid precursor: Moiety capable of generating an amino acid residuefollowing incorporation of the precursor into a peptide.

Amplifying: Any process or combination of process steps that increasesthe number of copies of an identifier oligonucleotide. Amplification ofidentifier oligonucleotides can be carried out by any state of the artmethod including, but not limited to, a polymerase chain reaction toincrease the copy number of each identifier oligonucleotide by using theidentifier oligonucleotide(s) as template(s) for synthesising additionalcopies of the identifier oligonucleotides. Any amplification reaction orcombination of such reactions known in the art can be used asappropriate as readily recognized by those skilled in the art.Accordingly, identifier oligonucleotides can be amplified using apolymerase chain reaction (PCR), a ligase chain reaction (LCR), by invivo amplification of identifier oligonucleotides cloned in DNAchromosomal or extra-chromosomal elements including vectors andplasmids, and the like. The amplification method should preferablyresult in the proportions of the amplified mixture of identifieroligonucleotides being essentially representative of the proportions ofidentifier oligonucleotides of different sequences in a mixture prior tosaid amplification.

Base: Nitrogeneous base moiety of a natural or non-natural nucleotide,or a derivative of such a nucleotide comprising alternative sugar orphosphate moieties. Base moieties include any moiety that is differentfrom a naturally occurring moiety and capable of complementing one ormore bases of the opposite nucleotide strand of a double helix.

Bifunctional complex: Molecule linked to an identifier oligonucleotidecapable of identifying the molecule and/or the reactants havingparticipated in the synthesis of the molecule. An “intermediatebifunctional complex” wherein the chemical reaction site or the(precursor) molecule part will undergo further reactions with reactantsor chemical entities in order to synthesise a “final” molecule is alsotermed a “nascent bifunctional complex”.

Binding region: Region on a string of consecutive nucleotides to whichan enzyme can bind, e.g. when ligating different oligonucleotides (e.g.in case of a ligase) or prior to a fill-in reaction (e.g. in case of apolymerase).

Catalyst: Moiety acting on a starting compound or a set of startingcompounds and speeding up chemical reactions involving such compound(s).

Chemical entity: Functional chemical group, or reactant, which, whenreacted, becomes covalently attached to a site, such as a chemicalreaction site, for example a site on a molecule, such as a scaffold atwhich site one or more reactive groups can be e.g. reacted, substitutedor added. Chemical entities and reactants are used interchangably hereinin bond-forming reactions resulting in the formation of a molecule, or amolecule precursor. For example, a carbon atom that is part of thescaffold can be bound to a methyl group chemical entity. This site mayalso be within the scaffold; for example, a hydrogen atom on a carbonatom within a ring can be a chemical entity. Chemical entities canpreferably be modified or replaced by other chemical entities or derivedsubstituents using one step or two step chemical processes. Protectionand de-protection steps may also be required. In an embodiment of themethods of the invention, this modification can be done independently ateach chemical entity, without the need to add protecting groups at theother chemical entities. Chemical entities may comprise substituentscapable of anomalous scattering. The chemical entity either forms partof a reactant or is used herein interchangably with the term “reactant”.The chemical entity can comprise or be linked to a reactive groupcapable of reacting with reactive groups of other chemical entities orreactants. Chemical entities that can be used in some aspects of thepresent invention include, but are not limited to H, benzyl halide,benzyl alcohol, allyl halide, allyl alcohol, carboxylic acid, arylamine, heteroaryl amine, benzyl amine, aryl alkyl amine, alkyl amino,phenol, aryl halide, heteroaryl halide, heteroaryl chloride, arylaldehyde, heteroaryl aldehyde, aryl alkyl aldehyde, alkyl aldehyde,aryl, heteroaryl, alkyl, aryl alkyl, ketone, arylthiol, heteroarylthiol, urea, imide, aryl boronic acid, ester, carbamate, tert-butylcarbamate, nitro, aryl methyl, heteroaryl methyl, vinyl methyl, 2- or2,2-substituted vinyls, 2-substituted alkynes, acyl halide, aryl halide,alkyl halide, cycloalkyl halide, sulfonyl halide, carboxylic anhydride,epoxide, and sulfonic acid. In some embodiments, the chemical entitiesmay include, but are not limited to benzyl bromide, benzyl alcohol,allyl bromide, allyl alcohol, carboxylic acid, aryl amine, heteroarylamine, benzyl amine, aryl alkyl amine, phenol, aryl bromide, heteroarylbromide, heteroaryl chloride, aryl aldehyde, heteroaryl aldehyde, arylalkyl aldehyde, ketone, arylthiol, heteroaryl thiol, urea, imide, andaryl boronic acid. Halide may include, for example, iodide, bromide,fluoride, and chloride. Halide may include halides capable of anomalousscattering, such as, for example, bromide or iodide. By convention, achemical entity can be considered as either “direct” chemical entitiesor “latent” chemical entities, with some having the capacity to functionas either. A direct chemical entity is a functional group or moiety thatcan react directly with another functional group or moiety without priormodification or that can be rendered reactive by the addition ofreagents and/or catalysts typically, but not necessarily, in asingle-pot reaction. Examples of a direct chemical entity include, butare not limited to: the Br in a benzyl bromide, carboxylic acid, amine,phenol, the Br in an aryl bromide, aldehyde, thiol, boronic acid orester, and the like. A latent chemical entity is a functional group ormoiety that requires prior modification, either in a separate step afterwhich it may or may not be isolated, or generated in situ to afford amore reactive species (i.e., obtaining a direct chemical entity). Alatent chemical entity may also comprise a moiety that by virtue of itsproximity or connectivity to a functional group or other moiety isrendered reactive. Examples of a latent chemical entity include, but arenot limited to: nitro (which can be reduced to an amine), aryl methyl(which can be converted to aryl bromomethyl or to aryl carboxylic acid),olefin (which can undergo oxidative cleavage to afford an epoxide, analdehyde or carboxylic acid), and the like. The adoption of the aboveconvention serves to illustrate the scope of chemical moieties regardedas chemical entities within the present invention. Additional chemicalentities are within the scope of this invention and are evident to thosetrained in the art and having access to the chemical literature.

Chemical group: Entity of a reactant or chemical entity participating inthe synthesis of a molecule.

Chemical reaction site: Site of a nascent bifunctional complex reactedwith at least one reactant or chemical entity during the synthesis of amolecule.

Cleavable linker: Residue or bond capable of being cleaved underpredetermined conditions.

Cleaving: Breaking a chemical bond. The bond can be a covalent bond or anon-covalent bond.

Complementary binding partners: Binding partners capable of reactingwith each other. Binding partner and reactant are used interchangablyherein.

Complementary reactive groups: Reactive groups capable of reacting witheach other.

Contacting: Bringing e.g. corresponding reactive groups or correspondingbinding partners or hybridization partners into reactive contact witheach other. The reactive contact is evident from a reaction between thepartners, or the formation of a bond, or hybridization, between thepartners.

Cycle of reaction: The methods of the present invention employsplit-n-mix strategies for molecule synthesis. A reaction cycle involvesa reaction of a reactant or chemical entity with another reactant orchemical entity or with the chemical reaction site and the reaction of atag with another tag or with the priming site. In other words, areaction cycle involves both a molecule specific reaction and a tagspecific reaction.

Enzyme: Any polypeptide capable of speeding up chemical reactions.Enzymes act as catalysts for a single reaction and converts a startingcompound or a specific set of starting compounds into specific products.Examples are ligases and polymerases.

Hybridisation: The ability of complementary nucleotides to form anassociation through hydrogen bonding.

Identifier oligonucleotide: The identifier oligonucleotide can be singlestranded or, in an initial state, at least partly hybridised to one ormore discrete anti-tags. The oligonucleotide identifier (s) can belinear or branched. The nucleotides of the identifier oligonucleotidecan be natural and/or non-natural nucleotides, including nucleotidederivatives. The length can vary as long as the identifier is longenough (i.e. contains a sufficient number of nucleotides) to identifythe molecule part of the bifunctional complex to which the identifieroligonucleotide is linked, or the reactants having participated in thesynthesis of the molecule.

Interacting: Used interchangably with contacting. Bringing species suchas e.g. corresponding binding partners into reactive contact with eachother. The reaction can be mediated by recognition groups formingcorresponding binding partners by means of covalent or non-covalentbonds.

Library: A composition of different moieties, such as small molecules orbifunctional complexes comprising different small molecules each linkedto a specific identifier oligonucleotide identifying the small molecule.

Linker: A residue or chemical bond separating at least two species. Thespecies can be retained at an essentially fixed distance, or the linkercan be flexible and allow the species some freedom of movement inrelation to each other. The link can be a covalent bond or anon-covalent bond.

Molecule: A chemical reaction site, such as a scaffold, which hasreacted with one or more reactants. The molecule can form part of abifunctional complex further comprising an identifier oligonucleotidecapable of identifying the molecule or the reactants which have reactedin the method for synthesising the molecule. The molecule is also termeda “display molecule”. The molecule part of the bifunctional complex canbe linked covalently to the priming site of the bifunctional complexand/or to a single stranded identifier oligonucleotide comprising aplurality of covalently linked tags. A “molecule” is any chemicalentity, or part thereof, selected or designed to be part of a syntheticprecursor to lead candidate or drug candidate. The molecule comprisesone, two, or three or more chemical substituents, also called “chemicalentities”. A molecule preferably exhibits properties of desirable leadcompounds, including, for example, a low molecular complexity (lownumber of hydrogen bond donors and acceptors, low number of rotatablebonds, and low molecular weight), and low hydrophobicity. Because themolecule is small, one of ordinary skill in the art may further developor elaborate the molecule into a lead or drug candidate by modifying themolecule, either at the chemical entities or at the core structure, tohave desirable drug characteristics, including, for example, by meetingthe Lipinski rule of five. Preferred molecule properties includelead-like properties and are known to those of ordinary skill in the artand are described in Teague, S. J., et al., Agnew. Chem. Int. Ed.38:3743-3748, 1999; Oprea, T. I., et al., J. Chem. Inf. Comput. Sci.41:1308-1315, 2001; and Hann, M. M. et al., J. Chem. Inf. Comput. Sci.41:856-864, 2001. Desirable molecules include, but are not limited to,for example, molecules having many or all of the following generalproperties: MW<about 1000, MW<about 500, MW<about 350, MW<about 300, orMW<about 250, a clogP<about 3, less than about 5 rings, and anLogP<about 5 or <about 4. Other general properties may include less thanabout 15, such as 12, for example 10 nonterminal single bonds, less thanabout 10, such as 8, for example 6 hydrogen bond donors, and less thanabout 10, such as 8, for example 6 hydrogen bond acceptors. Thus,molecules are designed so that more complexity and weight can be addedduring development and building out of the compound into a leadcandidate, while maintaining the general properties. Molecules maycomprise scaffolds comprising cyclic or non-cyclic structures. Examplesof non-cyclic scaffolds, include, but are not limited to, hypusine,putrescine, gamma-aminobutyric acid, and 2-hydroxyputresine. Generally,the scaffold portion of a molecule may comprise 1) a cyclic structure,including any of the cyclic structures described herein, with 2) one ormore of the chemical entities disclosed herein.

Nascent bifunctional complex: Also referred to as a growing complex;specifies an initial or intermediate complex to be processed accordingto the methods of the present invention. An intermediate complexdesignates an initial complex that has been subjected to one or morerounds of reactant reaction and tag addition.

Natural nucleotide: Any of the four deoxyribonucleotides, dA, dG, dT,and dC (constituents of DNA) and the four ribonucleotides, A, G, U, andC (constituents of RNA) are natural nucleotides. Each natural nucleotidecomprises a sugar moiety (ribose or deoxyribose), a phosphate moiety,and a natural/standard base moiety. Natural nucleotides bind tocomplementary nucleotides according to well-known base pairing rules,such as e.g. Watson & Crick type base pairing, where adenine (A) pairswith thymine (T) or uracil (U); and where guanine (G) pairs withcytosine (C), wherein corresponding base-pairs are part ofcomplementary, anti-parallel nucleotide strands. The base pairingresults in a specific hybridization between predetermined andcomplementary nucleotides. The base pairing is the basis by whichenzymes are able to catalyze the synthesis of an oligonucleotidecomplementary to the template oligonucleotide. In this synthesis,building blocks (normally the triphosphates of ribo or deoxyriboderivatives of A, T, U, C, or G) are directed by a templateoligonucleotide to form a complementary oligonucleotide with thecorrect, complementary sequence. The recognition of an oligonucleotidesequence by its complementary sequence is mediated by corresponding andinteracting bases forming base pairs. In nature, the specificinteractions leading to base pairing are governed by the size of thebases and the pattern of hydrogen bond donors and acceptors of thebases. A large purine base (A or G) pairs with a small pyrimidine base(T, U or C). Additionally, base pair recognition between bases isinfluenced by hydrogen bonds formed between the bases. In the geometryof the Watson-Crick base pair, a six membered ring (a pyrimidine innatural oligonucleotides) is juxtaposed to a ring system composed of afused, six membered ring and a five membered ring (a purine in naturaloligonucleotides), with a middle hydrogen bond linking two ring atoms,and hydrogen bonds on either side joining functional groups appended toeach of the rings, with donor groups paired with acceptor groups.

Non-natural base pairing: Base pairing among non-natural nucleotides, oramong a natural nucleotide and a non-natural nucleotide. Examples aredescribed in U.S. Pat. No. 6,037,120, wherein eight non-standardnucleotides are described, and wherein the natural base has beenreplaced by a non-natural base. As is the case for natural nucleotides,the non-natural base pairs involve a monocyclic, six membered ringpairing with a fused, bicyclic heterocyclic ring system composed of afive member ring fused with a six membered ring. However, the patternsof hydrogen bonds through which the base pairing is established aredifferent from those found in the natural AT, AU and GC base pairs. Inthis expanded set of base pairs obeying the Watson-Crickhydrogen-bonding rules, A pairs with T (or U), G pairs with C, iso-Cpairs with iso-G, and K pairs with X, H pairs with J, and M pairs with N(FIG. 2). Nucleobases capable of base pairing without obeyingWatson-Crick hydrogen-bonding rules have also been described (Berger etal., 2000, Nucleic Acids Research, 28, pp. 2911-2914).

Non-natural nucleotide: Any nucleotide not falling within the abovedefinition of a natural nucleotide.

Nucleotide: The term nucleotides as used herein refers to both naturalnucleotides and non-natural nucleotides. Nucleotides can differ fromnatural nucleotides by having a different phosphate moiety and/or adifferent sugar moiety and/or a different base moiety from the naturalnucleotide. Accordingly, nucleotides can form part of an identifieroligonucleotide when they are linked to each other by a natural bond inthe form of a phosphodiester bond, or a non-natural bond, such as e.g. apeptide bond as in the case of PNA (peptide nucleic acids).

Nucleotide derivative: Nucleotide further comprising an appendedmolecular entity. The nucleotides can be derivatized on the bases and/orthe ribose/deoxyribose unit and/or the phosphate. Preferred sites ofderivatization on the bases include the 8-position of adenine, the5-position of uracil, the 5- or 6-position of cytosine, and the7-position of guanine. The nucleotide-analogs described below can bederivatized at the corresponding positions (Benner, U.S. Pat. No.6,037,120). Other sites of derivatization can be used, as long as thederivatization does not disrupt base pairing specificity. Preferredsites of derivatization on the ribose or deoxyribose moieties are the5′, 4′ or 2′ positions. In certain cases it can be desirable tostabilize the nucleic acids towards degradation, and it can beadvantageous to use 2′-modified nucleotides (U.S. Pat. No. 5,958,691).Again, other sites can be employed, as long as the base pairingspecificity is not disrupted. Finally, the phosphates can bederivatized. Preferred derivatizations are phosphorothiote. Nucleotideanalogs (as described below) can be derivatized similarly tonucleotides. It is clear that the various types of modificationsmentioned herein above, including i) derivatization and ii) substitutionof the natural bases or natural backbone structures with non-naturalbases and alternative, non-natural backbone structures, respectively,can be applied once or more than once within the same nucleic acidmolecule.

Oligonucleotide: The term oligonucleotide comprises oligonucleotides ofboth natural and/or non-natural nucleotides, including any combinationthereof. The natural and/or non-natural nucleotides can be linked bynatural phosphodiester bonds or by non-natural bonds. Oligonucleotideshave at least 2 nucleotides, such as 3 or more nucleotides.

Oligomer: Molecule comprising a plurality of monomers that can beidentical, of the same type, or different. Oligomers can behomooligomers comprising a plurality of identical monomers, oligomerscomprising different monomers of the same type, or heterooligomerscomprising different types of monomers, wherein each type of monomer canbe identical or different.

Partitioning: Process whereby molecules, or complexes comprising suchmolecules linked to an identifier oligonucleotide, are preferentiallybound to a target molecule and separated from molecules, or complexescomprising such molecules linked to an identifier oligonucleotide, thatdo not have an affinity for—and is consequently not bound to—such targetmolecules. Partitioning can be accomplished by various methods known inthe art. The only requirement is a means for separating molecules boundto a target molecule from molecules not bound to target molecules underthe same conditions. The choice of partitioning method will depend onproperties of the target and of the synthesised molecule and can be madeaccording to principles and properties known to those of ordinary skillin the art.

Peptide: Plurality of covalently linked amino acid residues defining asequence and linked by amide bonds. The term is used analogously witholigopeptide and polypeptide. The amino acids can be both natural aminoacids and non-natural amino acids, including any combination thereof.The natural and/or non-natural amino acids can be linked by peptidebonds or by non-peptide bonds. The term peptide also embracespost-translational modifications introduced by chemical orenzyme-catalyzed reactions, as are known in the art. Suchpost-translational modifications can be introduced prior topartitioning, if desired. Amino acids as specified herein willpreferentially be in the L-stereoisomeric form. Amino acid analogs canbe employed instead of the 20 naturally-occurring amino acids. Severalsuch analogs are known, including fluorophenylalanine, norleucine,azetidine-2-carboxylic acid, S-aminoethyl cysteine, 4-methyl tryptophanand the like.

Plurality: At least two.

Polymer: Molecules characterised by a sequence of covalently linkedresidues each comprising a functional group, including H. Polymersaccording to the invention comprise at least two residues.

Precursor entity: Chemical entity further comprising a precursor moietywhich is cleaved or modified when the chemical entity is reacted withanother chemical entity.

Priming site: Site on a display oligonucleotide or a nascentbifunctional complex to which at least on tag is added chemically orenzymatically or otherwise during the synthesis of the molecule. Atleast one tag is added enzymatically.

Reactive group: Part of a reactant and linked to the chemical entity ofthe reactant. Complementary reactive groups brought into reactivecontact with each other are capable of forming a chemical bond linkingtwo binding partners. Reaction of reactants comprising complementaryreactive groups result in the formation of a chemical bond between thereactants or the chemical entities of each reactant.

Recognition group: Part of a tag and involved in the recognition ofcomplementary recognitions groups of e.g. a complementaryoligonucleotide. Preferred recognition groups are natural andnon-natural nitrogeneous bases of a natural or non-natural nucleotide.

Recombine: A recombination process recombines two or more sequences by aprocess, the product of which is a sequence comprising sequences fromeach of the two or more sequences. When involving nucleotides, therecombination involves an exchange of nucleotide sequences between twoor more nucleotide molecules at sites of identical nucleotide sequences,or at sites of nucleotide sequences that are not identical, in whichcase the recombination can occur randomly. One type of recombinationamong nucleotide sequences is referred to in the art as gene shuffling.

Residue: A molecule comprises a plurality of linked residues, whereineach residue comprises a functional group. A polymer comprises asequence of covalently linked residues, wherein each residue comprises afunctional group.

Ribose derivative: Ribose moiety forming part of a nucleoside capable ofbeing enzymatically incorporated into a template or complementingtemplate. Examples include e.g. derivatives distinguishing the ribosederivative from the riboses of natural ribonucleosides, includingadenosine (A), guanosine (G), uridine (U) and cytidine (C). Furtherexamples of ribose derivatives are described in e.g. U.S. Pat. No.5,786,461. The term covers derivatives of deoxyriboses, and analogouslywith the above-mentioned disclosure, derivatives in this casedistinguishes the deoxyribose derivative from the deoxyriboses ofnatural deoxyribonucleosides, including deoxyadenosine (dA),deoxyguanosine (dG), deoxythymidine (dT) and deoxycytidine (dC).

Scaffold: Structural entity comprising one or more reactive groups,preferably more reactive groups, with which one or more reactants canreact. A “scaffold” or “core scaffold” is a molecule that generally doesnot include chemical entities, as described herein, but may includeinternal chemical entities, such as atoms that are part of one of thecentral rings. A molecule comprises a scaffold and at least one chemicalentity. Non-limiting examples of a scaffold include any cyclic ornon-cyclic structure, such as, but not limited to, those disclosedherein. In some embodiments of the invention, a scaffold is the portionof a molecule lacking one or more chemical entities. Compounds of theinvention include those comprising a scaffold and one or more chemicalentities. A scaffold preferably exhibits properties of desirable leadcompounds, including, for example, a low molecular complexity (lownumber of hydrogen bond donors and acceptors, low number of rotatablebonds, and low molecular weight), and low hydrophobicity. Because ascaffold is small, one of ordinary skill in the art may further developor elaborate the core into a lead or drug candidate by modifying thecore to have desirable drug characteristics, including, for example, bymeeting the Lipinski rule of five. Preferred core properties includelead-like properties and are known to those of ordinary skill in the artand are described in Teague, S. J., et al., Agnew. Chem. Int. Ed.38:3743-3748, 1999; Oprea, T. I., et al., J. Chem. Inf. Comput. Sci.41:1308-1315, 2001; and Hann, M. M. et al., J. Chem. Inf. Comput. Sci.41:856-864, 2001. Thus, scaffolds are designed so that more complexityand weight can be added during development and building out of themolecule into a lead candidate, while maintaining the generalproperties.

Selectively cleavable linker: A selectively cleavable linkers are notcleavable under conditions wherein cleavable linkers is cleaved.

Specific recognition: The specific interaction of e.g. a nucleotide of atag with preferably one predetermined nucleotide of an anti-tagconstitutes a specific recognition. A specific recognition occurs whenthe affinity of a tag nucleotide recognition group for an anti-tagnucleotide recognition group results in the formation of predominantlyonly one type of corresponding binding partners. Simple mis-matchincorporation does not exclude a specific recognition of correspondingbinding partners.

Subunit: Monomer of a tag, such as e.g. a nucleotide.

Support: Solid or semi-solid member to which e.g. tags can be attached.Examples of supports includes planar surfaces including silicon wafersas well as beads.

Tag: Part of an identifier oligonucleotide. A tag is a string ofconsecutive nucleotides capable of identifying a particular reactanthaving reacted during the method of synthesising the molecule to whichthe identifier oligonucleotide is linked. A tag can be an element of anidentifier, such as an identifier oligonucleotide, comprising one ormore recognition group(s) capable of recognising one or morepredetermined, complementary recognition group(s). The recognition canbe generated by and/or result in the formation of a covalent bond or anon-covalent bond between corresponding pairs of recognition groupscapable of interacting with one another. The recognition groups can benucleobases in a strand of consecutive nucleotides, such as anoligonucleotide.

Tag complementation: Contacting a tag with a predetermined,complementary tag (anti-tag) comprising recognition group(s) capable ofrecognising the recognition groups(s) of the tag. Hybridisation ofcomplementary oligonucleotides (anti-tags) represents one example of atag complementation. The complementation occurs when a tag is broughtinto reactive contact with a predetermined, complementary tag capable ofrecognising the recognition group(s) of the tag. When the tag and thecomplementary tag (anti-tag) both comprises nucleotides, predeterminedsets of nucleotides are capable of complementing each other by means ofhydrogen bonds formed between the base moieties of the tags and theanti-tags capable of hybridising thereto.

Target molecule: Any compound of interest for which a templated moleculein the form of a ligand is desired. A target molecule can be a protein,fusion protein, peptide, enzyme, nucleic acid, nucleic acid bindingprotein, carbohydrate, polysaccharide, glycoprotein, hormone, receptor,receptor ligand, cell membrane component, antigen, antibody, virus,virus component, substrate, metabolite, transition state analog,cofactor, inhibitor, drug, controlled substance, dye, nutrient, growthfactor, toxin, lipid, glycolipid, etc., without limitation.

Variant: Molecule exhibiting a certain degree of identity orhomology—either physically or functionally—to a predetermined molecule.

The term “hydrido” denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form ahydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” and “alkylsulfonyl”, it embraces linear or branchedradicals having one to about twenty carbon atoms or, preferably, one toabout twelve carbon atoms. Preferred alkyl radicals are “lower alkyl”radicals having one to about ten carbon atoms, such as lower alkylradicals having one to about six carbon atoms. Examples of such radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. Branchedchain isomers of straight chain alkyl groups, include, but are notlimited to, the following which are provided by way of example:—CH(CH₃)₂, —CH(CH₃) (CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃,—CH₂CH(CH₃)₂, —CH₂CH(CH₃) (CH₂CH₃), —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃,—CH₂C(CH₂CH₃)₃, —CH(CH₃)CH(CH₃) (CH₂CH₃), —CH₂CH₂CH(CH₃)₂,—CH₂CH₂CH(CH₃) (CH₂CH₃), —CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃,—CH₂CH₂C(CH₂CH₃)₃, —CH(CH₃)CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)CH(CH₃)₂,—CH(CH₂CH₃)CH(CH₃)CH(CH₃) (CH₂CH₃), and others. When substituted, the“alkyl” or “lower alkyl” can comprise one or more radicals selected fromthe group of radicals consisting of hydroxy, primary amine, carboxy,acid chloride, sulfonyl chloride, sulphonate, nitro, cyano,isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl, carbonyl, andthiolyl.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twenty carbon atoms, suchas from two to about twelve carbon atoms, for example from two to abouteight carbon atoms. Preferred alkyl radicals are “lower alkenyl”radicals having two to about six carbon atoms. Examples of such radicalsinclude ethenyl, n-propenyl, butenyl, and the like. When substituted,the “alkenyl” or “lower alkenyl” can comprise one or more radicalsselected from the group of radicals consisting of hydroxy, primaryamine, carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro,cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms. The term “haloalkyl” embraces radicals wherein any one ormore of the alkyl carbon atoms is substituted with halo as definedabove. Specifically embraced are monohaloalkyl, dihaloalkyl andpolyhaloalkyl radicals. A monohaloalkyl radical, for one example, mayhave either an iodo, bromo, chloro or fluoro atom within the radical.Dihalo and polyhaloalkyl radicals may have two or more of the same haloatoms or a combination of different halo radicals. “Lower haloalkyl”preferably embraces radicals having 1-6 carbon atoms. Examples ofhaloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. The “haloalkyl” or“lower haloalkyl” can optionally be further substituted. When furthersubstituted, the “haloalkyl” or “lower haloalkyl” can further compriseone or more radicals selected from the group of radicals consisting ofhydroxy, primary amine, carboxy, acid chloride, sulfonyl chloride,sulphonate, nitro, cyano, isothiocyanate, phosphonyl, sulphonyl,sulfamyl, carbonyl, and thiolyl.

The term “hydroxyalkyl” embraces linear or branched alkyl radicalshaving from one to about ten carbon atoms any one of which may besubstituted with one or more hydroxyl radicals. Hydroxyalkyl radicalscan be “lower hydroxyalkyl” radicals preferably having one to six carbonatoms and one or more hydroxyl radicals. Examples of such radicalsinclude hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl. The “hydroxyalkyl” or “lower hydroxyalkyl” can optionallybe further substituted. When further substituted, the “hydroxyalkyl” or“lower hydroxyalkyl” can further comprise one or more radicals selectedfrom the group of radicals consisting of primary amine, carboxy, acidchloride, sulfonyl chloride, sulphonate, nitro, cyano, isothiocyanate,halogen, phosphonyl, sulphonyl, sulfamyl, carbonyl, and thiolyl.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy radical. Alkoxy radicals can be “loweralkoxy” radicals having one to six carbon atoms. Examples of suchradicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Theterm “alkoxyalkyl” also embraces alkyl radicals having two or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals. Alkoxyalkyl radicals can be“lower alkoxyalkyl” radicals having one to six carbon atoms and one ortwo alkoxy radicals. Examples of such radicals include methoxymethyl,methoxyethyl, ethoxyethyl, methoxybutyl and metoxypropyl. The alkyl insaid “alkoxyalkyl” can be substituted with one or more of hydroxy,primary amine, carboxy, acid chloride, sulfonyl chloride, sulphonate,nitro, cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl. When e.g. the above “alkoxyl” or “alkoxyalkyl”radicals are substituted with one or more halo atoms, such as fluoro,chloro or bromo, “haloalkoxy” or “haloalkoxyalkyl” radicals areprovided. Examples of such radicals include fluoromethoxy,chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy andfluoropropoxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. When substituted,“aryl” can comprise one or more radicals selected from the group ofradicals consisting of hydroxy, primary amine, carboxy, acid chloride,sulfonyl chloride, sulphonate, nitro, cyano, isothiocyanate, halogen,phosphonyl, sulphonyl, sulfamyl, carbonyl, and thiolyl. Examples of“aryl” include aromatic radicals such as phenyl, pentafluorphenyl,naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term “heterocyclic” embraces saturated, partially saturated andunsaturated heteroatom-containing ring-shaped radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. Whensubstituted, “heterocyclic” can comprise one or more radicals selectedfrom the group of radicals consisting of hydroxy, primary amine,carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro, cyano,isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl, carbonyl, andthiolyl. Examples of saturated heterocyclic radicals include e.g.saturated 3 to 6-membered heteromonocylic group containing 1 to 4nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.thiazolidinyl, etc.]. Examples of partially saturated heterocyclicradicals include dihydrothiophene, dihydropyran, dihydrofuran anddihydrothiazole.

The term “heteroaryl” embraces unsaturated heterocyclic radicals. Whensubstituted, “heteroaryl” can comprise one or more radicals selectedfrom the group of radicals consisting of hydroxy, primary amine,secondary amine, carboxy, acid chloride, sulfonyl chloride, sulphonate,nitro, cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl. Examples of unsaturated heterocyclic radicals,also termed “heteroaryl” radicals, include e.g. unsaturated 5 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.;unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term “heteroaryl” or “unsaturated heterocyclicradical” also embraces radicals where heterocyclic radicals are fusedwith aryl radicals. Examples of such fused bicyclic radicals includebenzofuran, benzothiophene, and the like. Said “heterocyclic group” canbe substituted with one or more radicals selected from the group ofradicals consisting of hydroxy, primary amine, carboxy, acid chloride,sulfonyl chloride, sulphonate, nitro, cyano, isothiocyanate, halogen,phosphonyl, sulphonyl, sulfamyl, carbonyl, and thiolyl, saidsubstitution generating a substituted “heteroaryl”, optionally asubstituted “heteroaryl” fused with an “aryl” radical which can besubstituted or un-substituted. When substituted, the “aryl” issubstituted as described herein above. Preferred heterocyclic radicalsinclude five to ten membered fused or unfused radicals. More preferredexamples or heteroaryl radicals include benzofuryl,2,3-dihydrobenzofuryl, benzotrienyl, indolyl, dihydroindolyl, chromanyl,benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl,pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical,where alkyl can be substituted is defined as above. Alkylsulfonylradicals can be “lower alkylsulfonyl” radicals having one to six carbonatoms. Examples of such lower alkylsulfonyl radicals includemethylsulfonyl, ethylsulfonyl and propylsulfonyl.

The term “arylsulfonyl” embraces aryl radicals as defined above,including substituted aryl radicals, attached to a sulfonyl radical.Examples of such radicals include phenylsulfonyl.

The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” whether aloneor used with terms such as “N-alkylaminosulfonyl”,“N-arylaminosulfonyl”, “N,N-dialkylaminosulfonyl” and“N-alkyl-N-arylaminosulfonyl”, denotes a sulfonyl radical substitutedwith an amine radical, forming a sulfonamide (—SO₂NH₂).

The terms “N-alkylaminosulfonyl” and “N,N-dialkylaminosulfonyl” denotesulfamyl radicals substituted respectively, with one alkyl radical, ortwo alkyl radicals, optionally substituted alkyl radicals as describedherein above. Alkylaminosulfonyl radicals can be “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Examples ofsuch lower alkylaminosulfonyl radicals include N-methylaminosulfonyl,N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl.

The terms “N-arylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl” denotesulfamyl radicals substituted, respectively, with one aryl radical, orone alkyl and one aryl radical, optionally substituted aryl and/or alkylradicals as described herein above. N-alkyl-N-arylaminosulfonyl radicalscan be “lower N-alkyl-N-arylsulfonyl” radicals having alkyl radicals ofone to six carbon atoms. Examples of such lower N-alkyl-N-arylaminosulfonyl radicals include N-methyl-phenylaminosulfonyl andN-ethyl-phenylaminosulfonyl.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The term “carboxyalkyl” or “alkanoyl” embraces radicals having a carboxyradical as defined above, attached to an alkyl radical as describedherein above. When substituted, the “alkyl” or “lower alkyl” cancomprise one or more radicals selected from the group of radicalsconsisting of hydroxy, primary amine, carboxy, acid chloride, sulfonylchloride, sulphonate, nitro, cyano, isothiocyanate, halogen, phosphonyl,sulphonyl, sulfamyl, carbonyl, and thiolyl. Examples of “carboxyalkyl”radicals include formyl, acetyl, propionyl (propanoyl), butanoyl(butyryl), isobutanoyl (isobutyryl), valeryl (pentanoyl), isovaleryl,pivaloyl, hexanoyl or the like.

The term “carbonyl”, whether used alone or with other terms, such as“alkylcarbonyl”, denotes —(C═O)—.

The term “alkylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with an alkyl radical. Alkylcarbonyl radicals can be “loweralkylcarbonyl” radicals having from one to six carbon atoms. Examples ofsuch radicals include methylcarbonyl and ethylcarbonyl. Whensubstituted, the “alkyl” or “lower alkyl” of the “alkylcarbonyl” cancomprise one or more radicals selected from the group of radicalsconsisting of hydroxy, primary amine, carboxy, acid chloride, sulfonylchloride, sulphonate, nitro, cyano, isothiocyanate, halogen, phosphonyl,sulphonyl, sulfamyl, and thiolyl.

The term “alkylcarbonylalkyl”, denotes an alkyl radical substituted withan “alkylcarbonyl” radical as described herein above. Both the alkyl andthe alkylcarbonyl can be substituted as described herein above.

The term “alkoxycarbonyl” means a radical containing an alkoxy radical,as defined above, attached via an oxygen atom to a carbonyl radical.“Lower alkoxycarbonyl” embraces alkoxy radicals preferably having fromone to six carbon atoms. Examples of “lower alkoxycarbonyl” esterradicals include substituted or unsubstituted methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.

The term “alkoxycarbonylalkyl” embraces radicals having“alkoxycarbonyl”, as defined above substituted to an optionallysubstituted alkyl radical. Alkoxycarbonylalkyl radicals can be “loweralkoxycarbonylalkyl” having lower alkoxycarbonyl radicals as definedabove attached to one to six carbon atoms. Examples of such loweralkoxycarbonylalkyl radicals include methoxycarbonylmethyl,tert-butoxycarbonylethyl, and methoxycarbonylethyl.

The term “aminocarbonyl” when used by itself or with other terms such as“aminocarbonylalkyl”, “N-alkylaminocarbonyl”, “N-arylaminocarbonyl”,“N,N-dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”,“N-alkyl-N-hydroxyaminocarbonyl” and“N-alkyl-N-hydroxyaminocarbonylalkyl”, denotes an amide group of theformula —C(═O)NH₂.

The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denoteaminocarbonyl radicals which have been substituted with one alkylradical and with two alkyl radicals, respectively. The alkyl radicalscan be substituted as described herein above. “Lower alkylaminocarbonyl”comprises lower alkyl radicals as described above attached to anaminocarbonyl radical.

The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical, wherein such radicals can besubstituted as described herein above.

The term “aminocarbonylalkyl” embraces optionally substituted alkylradicals substituted with aminocarbonyl radicals.

The term “N-cycloalkylaminocarbonyl” denotes aminocarbonyl radicalswhich have been substituted with at least one optionally substitutedcycloalkyl radical. “Lower cycloalkylaminocarbonyl” comprises lowercycloalkyl radicals of three to seven carbon atoms, attached to anaminocarbonyl radical.

The term “aminoalkyl” embraces alkyl radicals substituted with one ormore amino radicals. The alkyl radicals can be further substituted byone or more radicals selected from the group of radicals consisting ofhydroxy, carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro,cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl.

The term “alkylaminoalkyl” embraces aminoalkyl radicals having thenitrogen atom substituted with an optionally substituted alkyl radical.

The term “amidino” denotes an —C(═NH)—NH₂ radical.

The term “cyanoamidino” denotes an —C(═N—CN)—NH₂ radical.

The term “heterocyclicalkyl” embraces heterocyclic-substituted alkylradicals. The alkyl radicals can themselves be substituted by one ormore radicals selected from the group of radicals consisting of hydroxy,primary amino, carboxy, acid chloride, sulfonyl chloride, sulphonate,nitro, cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl. Heterocyclicalkyl radicals can be “lowerheterocyclicalkyl” radicals preferably having from one to six carbonatoms and a heterocyclic radical. Examples include such radicals aspyrrolidinylmethyl, pyridylmethyl and thienylmethyl.

The term “aralkyl” embraces aryl-substituted alkyl radicals. The alkylradicals can themselves be substituted by one or more radicals selectedfrom the group of radicals consisting of hydroxy, primary amino,carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro, cyano,isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl, carbonyl, andthiolyl. Aralkyl radicals can be “lower aralkyl” radicals having arylradicals attached to alkyl radicals having from one to six carbon atoms.Examples of such radicals include benzyl, diphenylmethyl,triphenylmethyl, phenylethyl and diphenylethyl. The aryl in said aralkylmay be additionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy. The terms benzyl and phenylmethyl are interchangeable.

The term “cycloalkyl” embraces radicals having three to ten carbonatoms. Cycloalkyl radicals can be “lower cycloalkyl” radicals havingthree to seven carbon atoms. Examples include radicals such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The“cycloalkyl” can optionally be substituted by one or more radicalsselected from the group of radicals consisting of hydroxy, primaryamine, carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro,cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl.

The term “cycloalkenyl” embraces unsaturated cyclic radicals havingthree to ten carbon atoms. The “cycloalkenyl” can optionally besubstituted by one or more radicals selected from the group of radicalsconsisting of hydroxy, primary amine, carboxy, acid chloride, sulfonylchloride, sulphonate, nitro, cyano, isothiocyanate, halogen, phosphonyl,sulphonyl, sulfamyl, carbonyl, and thiolyl. Examples includecyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, which canoptionally be substituted as described above.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. An example of “alkylthio” is methylthio, (CH₃—S—). The alkylradical can be substituted as described herein above.

The term “alkylsulfinyl” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, attached to adivalent —S(═O)— atom. The alkyl radical can be substituted as describedherein above.

The term “aminoalkyl” embraces alkyl radicals substituted with aminoradicals. The alkyl radicals can be further substituted by one or moreradicals selected from the group of radicals consisting of hydroxy,carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro, cyano,isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl, carbonyl, andthiolyl. Aminoalkyl radicals can be “lower aminoalkyl” having from oneto six carbon atoms. Examples include aminomethyl, aminoethyl andaminobutyl which can optionally be further substituted as describedabove.

The term “alkylaminoalkyl” embraces aminoalkyl radicals having thenitrogen atom substituted with at least one alkyl radical.Alkylaminoalkyl radicals can be “lower alkylaminoalkyl” having one tosix carbon atoms attached to a lower aminoalkyl radical as describedabove. The alkyl radical can be substituted as described herein above.

The terms “N-alkylamino” and “N,N-dialkylamino” denote amino groupswhich have been substituted with one alkyl radical and with two alkylradicals, respectively. The alkyl radical can be substituted asdescribed herein above. Alkylamino radicals can be “lower alkylamino”radicals having one or two alkyl radicals of one to six carbon atoms,attached to a nitrogen atom. Suitable “alkylamino” may be mono ordialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “arylamino” denotes amino groups which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The “arylamino”radicals may be further substituted on the aryl ring portion of theradical. Substitutions can include one or more of hydroxy, amino,carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro, cyano,isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl, carbonyl, andthiolyl.

The term “aralkylamino” denotes amino groups which have been substitutedwith one or two aralkyl radicals, such as N-benzylamino. The“aralkylamino” radicals may be further substituted on the aryl ringportion of the radical. Substitutions can include one or more ofhydroxy, amino, carboxy, acid chloride, sulfonyl chloride, sulphonate,nitro, cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl.

The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denoteamino groups which have been substituted with one aralkyl and one alkylradical, or one aryl and one alkyl radical, respectively, to an aminogroup. The aralkyl and/or alkyl and/or aryl radicals can be substitutedas described herein above.

The terms “N-arylaminoalkyl” and “N-aralkylaminoalkyl” denote aminogroups which have been substituted with one aryl radicals or one aralkylradical, respectively, and having the amino group attached to an alkylradical. The aralkyl and/or alkyl and/or aryl radicals can besubstituted as described herein above. Arylaminoalkyl radicals can be“lower arylaminoalkyl” having the arylamino radical attached to one tosix carbon atoms. Examples of such radicals include N-phenylaminomethyland N-phenyl-N-methylaminomethyl.

The terms “N-alkyl-N-arylaminoalkyl”, and “N-aralkyl-N-alkylaminoalkyl”denote N-alkyl-N-arylamino and N-alkyl-N-aralkylamino groups,respectively, and having the amino group attached to alkyl radicalswhich can be substituted as described herein above.

The term “acyl”, whether used alone, or within a term such as“acylamino”, denotes a radical provided by the residue after removal ofhydroxyl from an organic acid. The term “acylamino” embraces an aminoradical substituted with an acyl group. An examples of an “acylamino”radical is acetylamino or acetamido (CH₃C(═O)—NH—) where the amine maybe further substituted with alkyl, aryl or aralkyl, wherein said alkyl,aryl or aralkyl can be substituted as described herein above. The term“arylthio” embraces aryl radicals of six to ten carbon atoms, attachedto a divalent sulfur atom. The aryl can be substituted as describedherein above. An example of “arylthio” is phenylthio.

The term “aralkylthio” embraces aralkyl radicals as described above,attached to a divalent sulfur atom. The aralkyl radicals can be furthersubstituted as described herein above. An example of “aralkylthio” isbenzylthio.

The term “aryloxy” embraces aryl radicals, as defined above, attached toan oxygen atom. The aryl can be substituted as described herein above.Examples of such radicals include phenoxy.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. The aralkyl can be substitutedas described herein above. Aralkoxy radicals can be “lower aralkoxy”radicals having phenyl radicals attached to lower alkoxy radical asdescribed above.

The term “haloaralkyl” embraces aryl radicals as defined above attachedto haloalkyl radicals. The aryl can be further substituted as describedherein above.

The term “carboxyhaloalkyl” embraces carboxyalkyl radicals as definedabove having halo radicals attached to the alkyl portion. The alkylportion can be further substituted as described herein above.

The term “alkoxycarbonylhaloalkyl” embraces alkoxycarbonyl radicals asdefined above substituted on a haloalkyl radical. The haloalkyl radicalcan be further substituted by one or more of hydroxy, amino, carboxy,acid chloride, sulfonyl chloride, sulphonate, nitro, cyano,isothiocyanate, phosphonyl, sulphonyl, sulfamyl, carbonyl, and thiolyl.

The term “aminocarbonylhaloalkyl” embraces aminocarbonyl radicals asdefined above substituted on an optionally substituted haloalkyl radicalwherein the alkyl is substituted by one or more of hydroxy, amino,carboxy, acid chloride, sulfonyl chloride, sulphonate, nitro, cyano,isothiocyanate, phosphonyl, sulphonyl, sulfamyl, carbonyl, and thiolyl.

The term “alkylaminocarbonylhaloalkyl” embraces alkylaminocarbonylradicals as defined above substituted on an optionally substitutedhaloalkyl radical as described above.

The term “alkoxycarbonylcyanoalkenyl” embraces alkoxycarbonyl radicalsas defined above, and a cyano radical, both substituted on an optionallysubstituted alkenyl radical.

The term “carboxyalkylaminocarbonyl” embraces aminocarbonyl radicalssubstituted with carboxyalkyl radicals, as defined above. Thecarboxyalkyl can be further substituted. Substitutions can include oneor more of hydroxy, amino, acid chloride, sulfonyl chloride, sulphonate,nitro, cyano, isothiocyanate, halogen, phosphonyl, sulphonyl, sulfamyl,carbonyl, and thiolyl.

The term “aralkoxycarbonylalkylaminocarbonyl” embraces aminocarbonylradicals substituted with aryl-substituted alkoxycarbonyl radicals, asdefined above.

The term “cycloalkylalkyl” embraces cycloalkyl radicals having three toten carbon atoms attached to an alkyl radical, as defined above.Cycloalkylalkyl radicals can be “lower cycloalkylalkyl” radicals havingcycloalkyl radicals attached to lower alkyl radicals as defined above.Examples include radicals such as cyclopropylmethyl, cyclobutylmethyl,and cyclohexylethyl.

The term “aralkenyl” embraces optionally substituted aryl radicalsattached to alkenyl radicals having two to ten carbon atoms, such asphenylbutenyl, and phenylethenyl or styryl. When substituted the arylcan be substituted with one or more of hydroxy, amino, carboxy, acidchloride, sulfonyl chloride, sulphonate, nitro, cyano, isothiocyanate,halogen, phosphonyl, sulphonyl, sulfamyl, carbonyl, and thiolyl.

BRIEF DISCLOSURE OF THE FIGURES

FIG. 1. A tag addition process employing linkage of top strand tagsonly. (a) The initial bifunctional complex. (b-e) Addition of tags A toD. (f) The top strand containing tags A to D. (h) The individualanti-tags Ax to Dx. The polarity of overhangs is such that B, C, and Dtags contact their cognant anti-tag and the anti-tag cognate to thefollowing tag, e.g. a B-tag contacts an anti-B-tag and an anti-C-tag.

FIG. 2. One possible type of tag layout. (a) The initial bifunctionalcomplex containing a chemical reaction site, a linker moiety, and a tagregion (linker tag). (b) Tags A, B, C, and D containing a tag region andan overhang region. (c) The anti-A-tag containing an anti-linker tagregion and an anti-A-tag region. (d) Anti-tags Ax, Bx, Cx, and Dxcontaining an anti-overhang region and an anti-tag region.

FIG. 3. A tag addition process employing linkage of top strand tags onlyand using non-abutting anti-tags, i.e., the anti-tags are separated fromeach other. (a) The initial bifunctional complex. (b-e) Addition of tagsA to D. (f) The top strand containing tags A to D. (h) The individualanti-tags Ax to Dx. The polarity of overhangs is such that B, C, and Dtags contact their cognant anti-tag and the anti-tag cognate to thefollowing tag, e.g. a B-tag contacts an anti-B-tag and an anti-C-tag.

FIG. 4. Different possible designs of the initial bifunctional complex.(a) a single chemical reaction site is attached to a single linker tagvia a non-branched linker. (b) A number (n) of chemical reaction sitesare attached to a single linker tag via a branched linker. (c) A singlechemical reaction site is attached to a number (n) of linker tags via abranched linker. (d) A number (n) of chemical reaction sites areattached to a number (n) of linker tags via a branched linker.

FIG. 5. A tag addition process employing linkage of top strand tagsonly. (a) The initial bifunctional complex. (b-e) Addition of tags A toD. (f) The top strand containing tags A to D. (h) The individualanti-tags Ax to Dx. The polarity of overhangs is such that B, C, and Dtags contact their cognant anti-tag and the anti-tag cognate to theprevious tag (compare with FIG. 1), e.g. a B-tag contacts an anti-B-tagand an anti-A-tag.

FIG. 6. A tag addition process employing linkage of top strand tags onlyand removal of anti-tags after each cycle of tag addition. (a) Theinitial bifunctional complex. (b-e) Addition of tags A to D. (f) The topstrand containing tags A to D. The polarity of overhangs is such that B,C, and D tags contact their cognant anti-tag and the anti-tag cognate tothe following tag, e.g. a B-tag contacts an anti-B-tag and ananti-C-tag.

FIG. 7. The primer extension process. (a) An extension primer isannealed to the single tag strand containing tags. (b) Extension of theprimer results in a double-stranded tag.

FIG. 8. Examples of chemical reactions using an amine as a chemicalreaction site.

FIG. 9. Examples of chemical reactions using an acid as a chemicalreaction site.

FIG. 10. Examples of chemical reactions using an aldehyde or a ketone asa chemical reaction site.

FIG. 11. Examples of chemical reactions using Wittig orHorner-Wadsworth-Emmons reaction substrates.

FIG. 12. Examples of chemical reactions generating a dinucleophile.

FIG. 13. Examples of monofunctional versus multifunctional reactions.(a) monofunctional reaction. (b) bifunctional reaction generating aheterocyclic molecule.

FIG. 14. Examples of bifunctional electrophiles.

FIG. 15. Examples of chemical reactions of 1,2-dielectrophiles.

FIG. 16. Examples of chemical reactions of 1,3-dielectrophiles.

FIG. 17. Examples of transformations of building blocks (reactants) intoheterocycles.

FIG. 18. Examples of heterocyclic structures generated usingbifunctional reactions.

FIG. 19. Examples of chemical reactions generating bicyclic structures(I).

FIG. 20. Examples of chemical reactions generating bicyclic structures(II).

FIG. 21. Examples of chemical reaction matrix illustrating how buildingblocks (reactants) (rows and columns) can be combined to form cyclicstructures.

FIGS. 22-23. The figures serve to illustrate the formation ofmolecules/product structures formed by the process.

The figures represent examples, which are not meant to limit the scopeof the invention. In FIG. 22, the following steps are illustrated:

Step i.: E.g. enzymatical ligation of one oligonucleotide tag to thedisplay oligonucleotide.

Step ii.: E.g. Reacting one reactant with the chemical reaction site inthe formation of one or more covalent bonds.

Step iii.: Reactive groups may optionally be transformed into otherreactive groups, such as for example but not limited to the deprotectionof one reactive group into another reactive group, for exampledeprotection of a amino protection group, whereby a reactive amine willbe formed, for example deprotection of an ester, whereby a reactivecarboxylic acid will be formed, for example oxidation of a 1,2-diolusing periodate, whereby a reactive aldehyde will be formed.

Step iv.: Optionally repeat step iii., optionally repeat step i. and ii.Optionally, conduct further repetition of step iv. and other steps inaccordance with and as described and claimed by this invention.

FIG. 23. Reactants may be reacted prior to (step ii) reactions with thechemical reaction site (step iii).

FIG. 24 The figure serves to illustrate example reactants comprising oneor more chemical entities and one or more reactive groups. The inventionis not limited to the use of the reactants shown. Reactants mayfurthermore be protected by use of one or more protection groups.

Reactants within a group comprising one or more identical reactivegroups may comprise different chemical entities, which may be focusedaround specific core structures or which may be diverse (different) orthe group may comprise a combination of focused and diverse chemicalentities.

Reactants in different groups of reactive groups may be focused aroundspecific core structures or may be diverse (different) or the groups maycomprise a combination of focused and diverse chemical entities.

FIGS. 25-36. Circles with a number inside, denotes reactants. Thefigures serve to illustrate various product structures formed by the useof reactants in various ways. Emphasized (thick) lines denotes a productstructure formed by the reaction of one or more reactive groups on oneor more reactants and a product structure formed by the reaction of oneor more reactive groups on one or more reactants and one or morechemical reaction sites. The product structure does not need to compriseatoms (direct covalent linkage of two reactants). The product structuremay also comprise one or more bonds and one or more atoms. The productstructure may be cyclic or linear or branched or combinations thereof.The product structure may for example also comprise product structureexamples as described elsewhere by this invention. Product structuresrepresented by thick lines may be the same or different.

FIGS. 37-50. In some figures a pyrimidine product structure is used asan example for a heteroaromatic chemical structure e.g. an azine, suchas for example a pyridine, a pyrimidine, a pyrazine, a pyridazine, apurine and for example benzo and azolo variants thereof. Azine productstructure examples are also exemplified elsewhere in this invention.

Definitions used:

CRS: Chemical Reactive Site

Chemical entities are denoted/illustrated by R groups, which may havenumbers such as R1, R2, R3, R4, R5, R6, R7, R8, R9, R10. Chemicalentities may also be shown as a circle with an R group inside. Suchcircles may optionally represent a cyclic structure, e.g. R1 may be acyclic structure such as e.g. a cyclic diamino acid, for example but notlimited to the product following the use of piperidine 2-carboxylic acidas reactant, whereby two amino groups may react with similar ordifferent electrophiles, such as for example reaction with aldehydesunder reductive amination conditions to form an alkylated amine, forexample reaction with a sulfonyl chloride to form sulfonamides, forexample acylation by reaction with carboxylic acids under for exampleEDC/NHS or DMTMM coupling conditions to form carboxamides, for examplereaction with haloazines to form aminoazines, and the carboxylic acid ofthe diaminoacid may undergo an acylation reaction to form an amide.Although illustrated by circles, the back bone/core/scaffolded structuremay in fact be either cyclic or non-cyclic, including branched, linear,cyclic structures or a combination thereof.

Amino groups may be primary amines, secondary amines, tertiary amines.Amide groups may be primary, secondary, tertiary amides. When the circlerepresents a cyclic structure, amines may be endocyclic or exocyclic.

Het: means a heterocyclic product structure for example an azine, anazole, a purine, and other heterocyclic systems as defined elsewhere inthe invention. Aromatic rings with an N inside the ring are bydefinition equivalent to Het. Pyrimidine structures are also equivalentto the definition of Het and the pyrimidine structure is only used toillustrate the example and not to limit the scope of this invention.

FIGS. 37-39. The figure describes various example product structuresformed by use of at least one reactant. In some examples reactantscomprising further reactive groups may react with further reactants toform linear, branched, cyclic, macrocyclic structures or a combinationthereof or undergo intramolecular cyclization through the reaction withfurther reactive groups on R1, including reactive groups not shown butcomprised by R1.

FIGS. 40-50. The figure describes various product structures formed byuse of 1-5 reactants, for example one reactant, for example 2 reactants,for example 3 reactants, for example 4 reactants, for example 5reactants. In some examples reactants comprising further reactive groupsmay react with further reactants to form linear, branched, cyclic ormacrocyclic structures or undergo intramolecular cyclization through thereaction with further reactive groups on Rn-groups, including reactivegroups not shown but comprised by Rn-groups (where n is an integer). Theinvention may also use more than five reactants, such as six reactants,for example seven reactants, for example eight reactants, for examplenine reactants, for example ten reactants. In another embodiment, 11-20reactants are used, such as 11-15 reactants, for example 16-20reactants.

FIG. 51. The figure illustrates a member of a tetramer libraryconsisting of bifunctional molecules each comprising 4 DNA codonelements (tags) covalently linked to the cognate chemical fragments. Theoverall structure of the bifunctional molecules is shown. Each 20 nt/bpcodon is spaced by a 10 nt fixed region and the tags A-D is flanked byfixed sequences useful for amplification by PCR.

FIG. 52. Panel A illustrates a single stranded identifieroligonucleotide linked to a reactive entity (chemical reaction site).Panel B illustrates iterative steps of subtraction of specificallyformed duplexes between the anti-tags supplied and the correspondingidentifier codon sequences.

FIG. 53. Illustration of a simple quadruple amino-DNA tag enablingsynthesis and display of the same encoded molecule attached to a singleencoding tag. It may be desirable to include spacing groups such aspolyethylene glycol (PEG) units at any point in the synthesis process(chosen by the experimenter) for improved synthesis and display of thesynthetic molecule.

FIG. 54. The figure depicts a scheme for the addition, by hybridization,of a helper molecule covalently linked to a DNA sequence complementaryto the region of DNA of the bifunctional library molecule that isproximal to the displayed molecule. Hybridization of a second primerfollowed by polymerase extention and ligation will produce dsDNAdisplaying both the encoded library molecule and the helper molecule

FIG. 55. In a split and mix library generation procedure n chemicalreactions are conducted producing n chemical fragments linked to Ndifferent tags producing intermediates with a common structure.

FIG. 56. The figure illustrates an alternative method for thepurification of the control mimics in the library is to include aselective cleavable linker connecting a handle for purification and thereactive chemical unit.

FIG. 57. The figure illustrates an alternative method for thepurification of the control mimics in a library. A selectively cleavablelinker connecting a handle for purification and the reactive chemicalunit is included. The reactive unit (site) is any suitable reactivegroups, for example, but not limited to, an amino, thiol,carboxylic-acid or aldehyde-group. The oligonucleotide moiety isoptional but provides an excellent handle for molecular weight analysisusing MS. The cleavable linker (optionally) is selectively cleavable byany means such as e.g. by enzymatic, chemical or photocleavable methods.The purification (optional) may be any unit capable of being selectivelyrecovered.

FIG. 58. The figure illustrates exemplary reaction chemistriesapplicable to the present invention.

DISCLOSURE OF THE INVENTION

The methods and products pertaining to the present invention are furtherdisclosed in more detail herein below. The examples demonstrating theutility of the present invention should not be construed as a limitationof the scope of protection conferred by the patent claims.

Nucleotides

A tag comprises recognition units, i.e. units which can be recognized byrecognition groups. The recognition units making up a tag possessesinformation so as to identify a reactant having participated in thesynthesis of the molecule. Generally, it is preferred that the tagcomprises or consists of a sequence of nucleotides.

Individual tags can be distinguished from each other e.g. by adifference in only a single nucleotide position, such as a deletion, aninsertion or a mutation. However, to facilitate a subsequent decodingprocess it is in general desirable to have two or more differences inthe nucleotide sequence of any two tags.

In the event two or more reactants are reacted with the chemicalreactive site, the tags of the identifier oligonucleotide can beseparated by a constant region or a binding region. One function of thebinding region can be to establish a platform at which an enzyme, suchas polymerase or ligase can recognise as a substrate. Depending on themolecule formed, the identifier oligonucleotide can comprise furthertags, such as 2, 3, 4, 5, or more tags. Each of the further tags can beseparated by a suitable binding region.

All or at least a majority of the tags of the identifier oligonucleotidecan be separated from a neighbouring tag by a binding sequence. Thebinding region may have any suitable number of nucleotides, e.g. 1 to20. The binding region, if present, may serve various purposes besidesserving as a substrate for an enzyme. In one setup of the invention, thebinding region identifies the position of the tag. Usually, the bindingregion either upstream or downstream of a tag comprises informationwhich allows determination of the position of the tag. In another setup,the binding regions have alternating sequences, allowing for addition ofreactants from two pools in the formation of the library. Moreover, thebinding region may adjust the annealing temperature to a desired level.

A binding region with high affinity can be provided by one or morenucleobases forming three hydrogen bonds to a cognate nucleobase.Examples of nucleobases having this property are guanine and cytosine.Alternatively, or in addition, the binding region can be subjected tobackbone modification. Several backbone modifications provides forhigher affinity, such as 2′-O-methyl substitution of the ribose moiety,peptide nucleic acids (PNA), and 2′-4′ O-methylene cyclisation of theribose moiety, also referred to as LNA (Locked Nucleic Acid).

The identifier oligonucleotide can optionally further comprise flankingregions around the tag. The flanking region can encompass a signalgroup, such as a fluorophor or a radio active group to allow fordetection of the presence or absence of a complex or the flanking regionmay comprise a label that can be detected, such as biotin. When theidentifier comprises a biotin moiety, the identifier may easily berecovered.

The flanking regions can also serve as priming sites for amplificationreactions, such as PCR. Usually, the last cycle in the formation of thebifunctional complex includes the incorporation of a priming site. Aregion of the bifunctional complex close to the molecule, such as anucleic acid sequence between the molecule and the tag coding for thescaffold molecule, is usually used for another priming site, therebyallowing for PCR amplification of the coding region of the bifunctionalcomplex.

Apart from a combination of the nucleotides coding for the identity ofthe reactant, a tag may comprise further nucleotides, such as a framingsequence. The framing sequence can serve various purposes, such asacting as a further annealing region for anti-tags and/or as a sequenceinformative of the point in time of the synthesis history of themolecule being synthesised.

In certain embodiments, a tag codes for several different reactants. Ina subsequent identification step, the structure of the molecule cannever-the-less be deduced by taking advantage of the knowledge of thedifferent attachment chemistries, steric hindrance, deprotection oforthogonal protection groups, etc. In another embodiment, the same tagis used for a group of reactants having a common property, such as alipophilic nature, molecular weight, or a certain attachment chemistry,etc. In a still further embodiment, each tag is unique, i.e. a similarcombination of nucleotides does not identify another reactant. The sameof different synthesis methods can employ the same or different type oftags as disclosed herein above.

In some embodiments it can be advantageous to use several different tagsfor the same reactant. Accordingly, two or more tags identifying thesame reactant can optionally carry further information relating to e.g.different reaction conditions.

The identifier oligonucleotide of the final bifunctional complexcomprises all the tags necessary for identifying the correspondingmolecule. All or part of the sequence of each tag is used to decipherthe structure of the reactants that have participated in the formationof the molecule, i.e. the reaction product.

The order of the tags can also be used to determine the order ofincorporation of the reactants. This can be of particular interest e.g.when a linear polymer is formed, because the exact sequence of thepolymer can be determined by decoding the encoding sequence. Usually, tofacilitate the decoding step, tags will further comprise a constantregion or a binding region together with the tag sequence identifying agiven reactant. The constant region may contain information about theposition of the reactant in a synthesis pathway resulting in thesynthesis of the molecule.

The identifier oligonucleotide of the bifunctional complex is in apreferred aspect of the invention amplifiable. The capability of beingamplified allows for the use of a low amount of bifunctional complexduring a selection process. In one embodiment the tag is a sequence ofnucleotides which can be amplified using standard techniques like PCR.When two or more tags are present in a linear identifyingoligonucleotide, said oligonucleotide generally comprises a certainbackbone structure, so as to allow an enzyme to recognise theoligonucleotide as substrate. As an example the back bone structure canbe DNA or RNA.

The priming site of a nascent bifunctional complex is capable ofreceiving a tag. When the tag comprises a polynucleotide sequence, thepriming site generally comprises a 3′-OH or 5′-phosphate group, orfunctional derivatives of such groups. Enzymes which can be used forenzymatic addition of a tag to the priming site include an enzymeselected from polymerase, ligase, and recombinase, and a combination ofthese enzymes. In some embodiments, an enzyme comprising ligase activityis preferred.

The display oligonucleotide provided in step i) of the above-citedmethod should be long enough to allow for hybridisation of an anti-tagthereto, c.f. step iv). A desirable length of the displayoligonucleotide is from about 3 consecutive nucleotides to about 25consecutive nucleotides, although longer display oligonucleotides canalso be provided. Accordingly, the display oligonucleotide preferablyhas from 5 to about 20 consecutive nucleotides, for example from 10 to20 consecutive nucleotides, such as 6 nucleotides, for example 7nucleotides, such as 8 nucleotides, for example 9 nucleotides, such as10 nucleotides, for example 11 nucleotides, such as 12 nucleotides, forexample 13 nucleotides, such as 14 nucleotides, for example 15nucleotides, such as 16 nucleotides, for example 17 nucleotides, such as18 nucleotides, for example 19 nucleotides.

Likewise, the each tag should be long enough to allow for hybridisationof one or two anti-tag(s) thereto, c.f. step iii). A desirable length ofa tag is from about 3 consecutive nucleotides to about 25 consecutivenucleotides, although longer tags can also be provided. Accordingly, thetags preferably have from 5 to about 20 consecutive nucleotides, such as6 nucleotides, for example 7 nucleotides, such as 8 nucleotides, forexample 9 nucleotides, such as 10 nucleotides, for example 11nucleotides, such as 12 nucleotides, for example 13 nucleotides, such as14 nucleotides, for example 15 nucleotides, such as 16 nucleotides, forexample 17 nucleotides, such as 18 nucleotides, for example 19nucleotides.

Likewise, the each anti-tag should be long enough to allow forhybridisation of one or two tag(s) thereto, c.f. step iv). A desirablelength of an anti-tag is from about 3 consecutive nucleotides to about25 consecutive nucleotides, although longer anti-tags can also beprovided. Accordingly, the anti-tags preferably have from 5 to about 20consecutive nucleotides, such as 6 nucleotides, for example 7nucleotides, such as 8 nucleotides, for example 9 nucleotides, such as10 nucleotides, for example 11 nucleotides, such as 12 nucleotides, forexample 13 nucleotides, such as 14 nucleotides, for example 15nucleotides, such as 16 nucleotides, for example 17 nucleotides, such as18 nucleotides, for example 19 nucleotides.

All or some of the nucleotides of a tag, or an anti-tag, can be involvedin the identification of a corresponding reactant. In other words,decoding of an identifier oligonucleotide can be performed bydetermining the sequence of all or only a part of the identifieroligonucleotide.

In some embodiments of the invention, each tag and each anti-tagconstitutes what is often referred to as a “codon” and an “anti-codon”,respectively. These terms are often used in the prior art even thoughthe methods employ split-n-mix technology and not templated reactions.In some embodiments, each tag and each anti-tag comprises one or more“codon(s)” or anti-codon(s)”, respectively, which identifies thecorresponding reactant involved in the synthesis of a molecule.

The single-stranded over-hangs resulting from hybridisation of tags andanti-tags can be of any suitable length as long as the over-hang allowsfor hybridisation of a tag or an anti-tag to the over-hang, c.f. stepsvi) and xii). A desirable length for an overhang is from about 3consecutive nucleotides to about 25 consecutive nucleotides, althoughlonger over-hangs can also be provided for. Accordingly, the over-hangspreferably have from 5 to about 20 consecutive nucleotides, such as 6nucleotides, for example 7 nucleotides, such as 8 nucleotides, forexample 9 nucleotides, such as 10 nucleotides, for example 11nucleotides, such as 12 nucleotides, for example 13 nucleotides, such as14 nucleotides, for example 15 nucleotides, such as 16 nucleotides, forexample 17 nucleotides, such as 18 nucleotides, for example 19nucleotides.

The identifier oligonucleotide resulting from tag ligation can includeor exclude the display oligonucleotide and preferably has a length offrom 6 to about 300 consecutive nucleotides, for example from 6 to about250 consecutive nucleotides, such as from 6 to about 200 consecutivenucleotides, for example from 6 to about 150 consecutive nucleotides,such as from 6 to 100, for example from 6 to 80, such as from 6 to 60,such as from 6 to 40, for example from 6 to 30, such as from 6 to 20,such as from 6 to 15, for example from 6 to 10, such as from 6 to 8,such as 6, for example from 7 to 100, such as from 7 to 80, for examplefrom 7 to 60, such as from 7 to 40, for example from 7 to 30, such asfrom 7 to 20, for example from 7 to 15, such as from 7 to 10, such asfrom 7 to 8, for example 7, for example from 8 to 100, such as from 8 to80, for example from 8 to 60, such as from 8 to 40, for example from 8to 30, such as from 8 to 20, for example from 8 to 15, such as from 8 to10, such as 8, for example 9, for example from 10 to 100, such as from10 to 80, for example from 10 to 60, such as from 10 to 40, for examplefrom 10 to 30, such as from 10 to 20, for example from 10 to 15, such asfrom 10 to 12, such as 10, for example from 12 to 100, such as from 12to 80, for example from 12 to 60, such as from 12 to 40, for examplefrom 12 to 30, such as from 12 to 20, for example from 12 to 15, such asfrom 14 to 100, such as from 14 to 80, for example from 14 to 60, suchas from 14 to 40, for example from 14 to 30, such as from 14 to 20, forexample from 14 to 16, such as from 16 to 100, such as from 16 to 80,for example from 16 to 60, such as from 16 to 40, for example from 16 to30, such as from 16 to 20, such as from 18 to 100, such as from 18 to80, for example from 18 to 60, such as from 18 to 40, for example from18 to 30, such as from 18 to 20, for example from 20 to 100, such asfrom 20 to 80, for example from 20 to 60, such as from 20 to 40, forexample from 20 to 30, such as from 20 to 25, for example from 22 to100, such as from 22 to 80, for example from 22 to 60, such as from 22to 40, for example from 22 to 30, such as from 22 to 25, for examplefrom 25 to 100, such as from 25 to 80, for example from 25 to 60, suchas from 25 to 40, for example from 25 to 30, such as from 30 to 100, forexample from 30 to 80, such as from 30 to 60, for example from 30 to 40,such as from 30 to 35, for example from 35 to 100, such as from 35 to80, for example from 35 to 60, such as from 35 to 40, for example from40 to 100, such as from 40 to 80, for example from 40 to 60, such asfrom 40 to 50, for example from 40 to 45, such as from 45 to 100, forexample from 45 to 80, such as from 45 to 60, for example from 45 to 50,such as from 50 to 100, for example from 50 to 80, such as from 50 to60, for example from 50 to 55, such as from 60 to 100, for example from60 to 80, such as from 60 to 70, for example from 70 to 100, such asfrom 70 to 90, for example from 70 to 80, such as from 80 to 100, forexample from 80 to 90, such as from 90 to 100 consecutive nucleotides.

The length of the identifier oligonucleotide will depend of the lengthof the individual tags as well as on the number of tags ligated. In someembodiments of the invention it is preferred that the identifieroligonucleotide is attached to a solid or semi-solid support.

The identifier oligonucleotide preferably comprises a string ofconsecutive nucleotides comprising from 2 to 10 tags, for example from 3to 10 tags, such as from 4 to 10 tags, for example from 5 to 10 tags,such as from 6 to 10 tags, for example from 7 to 10 tags, such as from 8to 10 tags, for example from 2 to 9 tags, such as from 2 to 8 tags, forexample from 2 to 7 tags, such as from 2 to 6 tags, for example from 2to 5 tags, such as from 2 to 4 tags, for example 2 or 3 tags, such asfrom 3 to 9 tags, such as from 3 to 8 tags, for example from 3 to 7tags, such as from 3 to 6 tags, for example from 3 to 5 tags, such asfrom 3 to 4 tags, for example from 4 to 9 tags, such as from 4 to 8tags, for example from 4 to 7 tags, such as from 4 to 6 tags, forexample from 4 to 5 tags, such as from 5 to 9 tags, such as from 5 to 8tags, for example from 5 to 7 tags, such as 5 or 6 tags, for example 2,3, 4 or 5 tags, such as 6, 7 or 8 tags, for example 9 or 10 tags.

The display oligonucleotide and/or the tags employed in the methods ofthe present invention in one embodiment preferably comprise oressentially consist of nucleotides selected from the group consisting ofdeoxyribonucleic acids (DNA), ribonucleic acids (RNA), peptide nucleicacids (PNA), locked nucleic acids (LNA), and morpholinos sequences,including any analog or derivative thereof.

In another embodiment, the display oligonucleotide and/or the tagsemployed in the methods of the present invention preferably comprise oressentially consist of nucleotides selected from the group consisting ofDNA, RNA, PNA, LNA and morpholinos sequence, including any analog orderivative thereof, and the anti-tags preferably comprise or essentiallyconsist of nucleotides selected from the group consisting of DNA, RNA,PNA, LNA and morpholinos sequences, including any analog or derivativethereof.

The nucleic acids useful in connection with the present inventioninclude, but is not limited to, nucleic acids which can be linkedtogether in a sequence of nucleotides, i.e. an oligonucleotide. However,in one embodiment and in order to prevent ligation of anti-tags, c.f.step xiv) and xv), end-positioned nucleic acids of anti-tags do notcontain a reactive group, such as a 5′-P or a 3′-OH reactive group,capable of being linked by e.g. an enzyme comprising ligase activity.The priming site of the display oligonucleotide preferably comprises a3′-OH or 5′-phosphate group, or functional derivatives of such groups,capable of being linked by an enzyme comprising ligase activity.

Each nucleotide monomer is normally composed of two parts, namely anucleobase moiety, and a backbone. The back bone may in some cases besubdivided into a sugar moiety and an internucleoside linker. Thenucleobase moiety can be selected among naturally occurring nucleobasesas well as non-naturally occurring nucleobases. Thus, “nucleobase”includes not only known purine and pyrimidine hetero-cycles, but alsoheterocyclic analogues and tautomers thereof. Illustrative examples ofnucleobases are adenine, guanine, thymine, cytosine, uracil, purine,xanthine, diaminopurine, 8-oxo-N-methyladenine, 7-deazaxanthine,7-deazaguanine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diamino-purine,5-methylcytosine, 5-(C³-C⁶)-alkynylcytosine, 5-fluorouracil,5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazolopyridine,isocytosine, isoguanine, inosine and the “non-natural” nucleobasesdescribed in U.S. Pat. No. 5,432,272.

The term “nucleobase” is intended to cover these examples as well asanalogues and tautomers thereof. Especially interesting nucleobases areadenine, guanine, thymine, cytosine, 5-methylcytosine, and uracil, whichare considered as the naturally occurring nucleobases. Examples ofsuitable specific pairs of nucleobases are shown below:

Suitable examples of backbone units are shown below (B denotes anucleobase):

The sugar moiety of the backbone is suitably a pentose, but can be theappropriate part of an PNA or a six-member ring. Suitable examples ofpossible pentoses include ribose, 2′-deoxyribose, 2′-O-methyl-ribose,2′-flour-ribose, and 2′-4′-O-methylene-ribose (LNA). Suitably thenucleobase is attached to the 1′ position of the pentose entity.

An internucleoside linker connects the 3′ end of preceding monomer to a5′ end of a succeeding monomer when the sugar moiety of the backbone isa pentose, like ribose or 2-deoxyribose. The internucleoside linkage canbe the natural occurring phosphodiester linkage or a derivative thereof.Examples of such derivatives include phosphorothioate,methylphosphonate, phosphoramidate, phosphotriester, andphosphodithioate. Furthermore, the internucleoside linker can be any ofa number of non-phosphorous-containing linkers known in the art.

Preferred nucleic acid monomers include naturally occurring nucleosidesforming part of the DNA as well as the RNA family connected throughphosphodiester linkages. The members of the DNA family includedeoxyadenosine, deoxyguanosine, deoxythymidine, and deoxycytidine. Themembers of the RNA family include adenosine, guanosine, uridine,cytidine, and inosine.

It is within the capability of the skilled person in the art toconstruct the desired design of an oligonucleotide. When a specificannealing temperature is desired it is a standard procedure to suggestappropriate compositions of nucleic acid monomers and the lengththereof. The construction of an appropriate design can be assisted bysoftware, such as Vector NTI Suite or the public database at theinternet address http://www.nwfsc.noaa.gov/protocols/oligoTMcalc.html.The conditions which allow hybridisation of two oligonucleotides areinfluenced by a number of factors including temperature, saltconcentration, type of buffer, and acidity. It is within thecapabilities of the person skilled in the art to select appropriateconditions to ensure that the contacting between two oligonucleotides isperformed at hybridisation conditions. The temperature at which twosingle stranded oligonucleotides forms a duplex is referred to as theannealing temperature or the melting temperature. The melting curve isusually not sharp indicating that the annealing occurs over atemperature range.

Oligonucleotides in the form of tags, anti-tags and displayoligonucleotides can be synthesized by a variety of chemistries as iswell known. For synthesis of an oligonucleotide on a substrate in thedirection of 3′ to 5′, a free hydroxy terminus is required that can beconveniently blocked and deblocked as needed. A preferred hydroxyterminus blocking group is a dimexothytrityl ether (DMT). DMT blockedtermini are first deblocked, such as by treatment with 3% dichloroaceticacid in dichloromethane (DCM) as is well known for oligonucleotidesynthesis, to form a free hydroxy terminus.

Nucleotides in precursor form for addition to a free hydroxy terminus inthe direction of 3′ to 5′ require a phosphoramidate moiety having anaminodiisopropyl side chain at the 3′ terminus of a nucleotide. Inaddition, the free hydroxy of the phosphoramidate is blocked with acyanoethyl ester (OCNET), and the 5′ terminus is blocked with a DMTether. The addition of a 5′ DMT-, 3′ OCNET-blocked phosphoramidatenucleotide to a free hydroxyl requires tetrazole in acetonitrilefollowed by iodine oxidation and capping of unreacted hydroxyls withacetic anhydride, as is well known for oligonucleotide synthesis. Theresulting product contains an added nucleotide residue with a DMTblocked 5′ terminus, ready for deblocking and addition of a subsequentblocked nucleotide as before.

For synthesis of an oligonucleotide in the direction of 5′ to 3′, a freehydroxy terminus on the linker is required as before. However, theblocked nucleotide to be added has the blocking chemistries reversed onits 5′ and 3′ termini to facilitate addition in the oppositeorientation. A nucleotide with a free 3′ hydroxyl and 5′ DMT ether isfirst blocked at the 3′ hydroxy terminus by reaction with TBS-CI inimidazole to form a TBS ester at the 3′ terminus. Then the DMT-blocked5′ terminus is deblocked with DCA in DCM as before to form a free 5′hydroxy terminus. The reagent (N,N-diisopropylamino) (cyanoethyl)phosphonamidic chloride having an aminodiisopropyl group and an OCNETester is reacted in tetrahydrofuran (THF) with the 5′ deblockednucleotide to form the aminodiisopropyl-, OCNET-blocked phosphonamidategroup on the 5′ terminus. Thereafter the 3′ TBS ester is removed withtetrabutylammonium fluoride (TBAF) in DCM to form a nucleotide with thephosphonamidate-blocked 5′ terminus and a free 3′ hydroxy terminus.Reaction in base with DMT-Cladds a DMT ether blocking group to the 3′hydroxy terminus.

The addition of the 3′ DMT-, 5′ OCNET-blocked phosphonamidatednucleotide to a linker substrate having a free hydroxy terminus thenproceeds using the previous tetrazole reaction, as is well known foroligonucleotide polymerization. The resulting product contains an addednucleotide residue with a DMT-blocked 3′ terminus, ready for deblockingwith DCA in DCM and the addition of a subsequent blocked nucleotide asbefore.

The identifier oligonucleotide part of a bifunctional complex is formedby addition of a tag or more than one tag to a priming site and/or to apreviously added tag using one or more enzymes such as enzymespossessing ligase activity. When one or more further tag(s) are attachedto a tag which was added to a nascent bifunctional complex in a previoussynthesis round, the addition can produce a linear or a branchedidentifier oligonucleotide. Preferably, at least one tag of theidentifier is attached to the priming site and/or to another tag by anenzymatically catalysed reaction, such as a ligation. Further tag(s) canin principle be attached using chemical means or enzymatic means. In oneembodiment, all tags are attached using an enzymatically catalysedreaction.

The identifier oligonucleotide part of the bifunctional complex ispreferably amplifiable. This means that the tags form a sequence ofnucleotides capable of being amplified e.g. using a polymerase chainreaction (PCR) techniques.

The tags can be “unique” for a single predetermined reactant, or a giventag can in principle code for several different reactants, in which casethe structure of the synthesised molecule can optionally be deduced bytaking into account factors such as different attachment chemistries,steric hindrance and deprotection of orthogonal protection groups. It isalso possible to use the same or similar tags for a group of reactantshaving at least one common property in common, such as e.g. lipophilicnature, molecular weight and attachment chemistry.

In one embodiment, two or more tags identifying the same reactantcomprise further information related to different reaction conditionsused for reacting said reactant. Individual tags can be distinguishedfrom each other by only a single nucleotide, or by two or morenucleotides. For example, when the tag or anti-tag length is 5nucleotides, more than 100 nucleotide combinations exist in which two ormore differences appear between any two tags.

Multiple Encoding

In one embodiment, multiple encoding implies that two or more tags areprovided in the identifier prior to or subsequent to a reaction betweenthe chemical reactive site and two or more reactants. Multiple encodinghas various advantages, such as allowing a broader range of reactionspossible, as many compounds can only be synthesis by a three (or more)component reaction because an intermediate between the first reactantand the chemical reactive site is not stable. Other advantages relatesto the use of organic solvents and the availability of two or morereactants in certain embodiments.

Thus in a certain aspect of the invention, it relates to a method forobtaining a bifunctional complex comprising a molecule part and aidentifier oligonucleotide, wherein the molecule is obtained by reactionof a chemical reactive site with two or more reactants and theidentifier oligonucleotide comprises tag(s) identifying the reactants.

In a certain aspect of the invention, a first reactant forms anintermediate product upon reaction with the chemical reactive site and asecond reactant reacts with the intermediate product to obtain themolecule or a precursor thereof. In another aspect of the invention, twoor more reactants react with each other to form an intermediate productand the chemical reactive site reacts with this intermediate product toobtain the molecule or a precursor thereof. The intermediate product canbe obtained by reacting the two or more reactants separately and then ina subsequent step reacting the intermediate product with the chemicalreactive site. Reacting the reactants in a separate step provide for thepossibility of using conditions the tags would not withstand. Thus, incase the identifier oligonucleotide comprises nucleic acids, thereaction between the reactant can be conducted at conditions thatotherwise would degrade the nucleic acid.

The reactions can be carried out in accordance with the scheme shownbelow. The scheme shows an example in which the identifying tags for tworeactants and the chemical reactive site (scaffold) attached to thechemical reaction site are provided in separate compartments. Thecompartments are arranged in an array, such as a microtiter plate,allowing for any combination of the different acylating agents and thedifferent alkylating agents.

Starting Situation:

Alkylating agents Acylating agents A B C . . . 1 Tagx11-X Tagx12-XTagx13-X . . . 2 Tagx21-X Tagx22-X Tagx23-X . . . 3 Tagx31-X Tagx32-XTagx33-X . . . . . . . . . . . . . . . . . . X denotes a chemicalreaction site such as a scaffold.

The two reactants are either separately reacted with each other in anycombination or subsequently added to each compartment in accordance withthe tags of the identifier oligonucleotide or the reactants can be addedin any order to each compartment to allow for a direct reaction. Thescheme below shows the result of the reaction.

Plate of Products

Alkylating agents Acylating agents A B C . . . 1 Tagx11-XA1 Tagx12-XB1Tagx13-XC1 . . . 2 Tagx21-XA2 Tagx22-XB2 Tagx23-XC2 . . . 3 Tagx31-XA3Tagx32-XB3 Tagx33-XC3 . . . . . . . . . . . . . . . . . .

As an example XA2 denotes molecule XA2 in its final state, i.e. fullyassembled from fragments X, A and 2.

The identifier oligonucleotide comprising the two or more tagsidentifying the reactants, can in principle be prepared in any suitableway either before or after the reaction. In one embodiment of theinvention, each of the identifier oligonucleotides are synthesised bystandard phosphoramidite chemistry. In another aspect the tags arepre-prepared and assembled into the final identifier oligonucleotide bychemical or enzymatic ligation.

Various possibilities for chemical ligation exist. Suitable examplesinclude that

a) a first oligonucleotide end comprises a 3′-OH group and the secondoligonucleotide end comprises a 5′-phosphor-2-imidazole group. Whenreacted a phosphodiester internucleoside linkage is formed,b) a first oligonucleotide end comprising a phosphoimidazolide group andthe 3′-end and a phosphoimidazolide group at the 5′- and. When reactedtogether a phosphodiester internucleoside linkage is formed,c) a first oligonucleotide end comprising a 3′-phosphorothioate groupand a second oligonucleotide comprising a 5′-iodine. When the two groupsare reacted a 3′-O—P(═O) (OH)—S-5′ internucleoside linkage is formed,andd) a first oligonucleotide end comprising a 3′-phosphorothioate groupand a second oligonucleotide comprising a 5′-tosylate. When reacted a3′-O—P(═O) (OH)—S-5′ internucleoside linkage is formed.

Enzymes

The identifier oligonucleotide of a nascent bifunctional complexinvolves the addition of at least one tag to a priming site using one ormore enzymes. Further tags can be attached to a previous tag so as toproduce a linear or branched identifier oligonucleotide. One or moreenzymes are used for at least one reaction involving one or moreidentifier oligonucleotide tags. Enzymes are in general substratespecific, entailing that the enzymatic addition of a tag to a primingsite, or to another tag, is not likely to interfere with the synthesisof a molecule. Enzymes can be active in both aqueous and organicsolvents.

As long as at least one tag of the identifier is attached to the primingsite or to another tag by an enzymatic reaction, further tags can beadded using either chemical means or the same or different enzymaticmeans. In one embodiment, all of the tags are added to the priming siteand/or to each other using the same or different enzymatically catalysedreaction(s).

In one embodiment, addition of a tag to the priming site, or to a taghaving reacted with the priming site or another tag in a previoussynthesis round, can involve an enzymatic extension reaction. Theextension reaction can be performed by a polymerase or a ligase, or acombination thereof. The extension using a polymerase is suitablyconducted using a tag hybridised to an anti-tag oligonucleotide astemplate. The substrate is usually a blend of triphosphate nucleotidesselected from the group comprising dATP, dGTP, dTTP, dCTP, rATP, rGTP,rTTP, rCTP, rUTP.

In a different embodiment, a ligase is used for the addition of a tagusing one or more oligonucleotides as substrates. The ligation can beperformed in a single stranded or a double stranded state depending onthe enzyme used. In general it is preferred to ligate tags in a doublestranded state, i.e. tag oligonucleotides to be ligated together arekept together by a complementing oligonucleotide (anti-tag), whichcomplements the ends of the two tag oligonucleotides to be ligated.

Substrates for ligases are oligo- and polynucleotides, i.e. nucleicacids comprising two or more nucleotides. An enzymatic ligation can beperformed in a single or double stranded fashion. When a single strandedligation is performed, a 3′ OH group of a first nucleic acid is ligatedto a 5′ phosphate group of a second nucleic acid. A double strandedligation uses a third oligonucleotide complementing a part of the 3′ endand 5′ end of the first and second nucleic acid to assist in theligation. Generally, it is preferred to perform a double strandedligation. Only tags are ligated. Anti-tags are not ligated as they donot, in one embodiment, comprise a reactive group, such as a 5′-P or a3′-OH, or variants or derivatives thereof, enabling enzymatic ligation.In another embodiment, anti-tags do not abut to each other but arephysically separated by hybridisation to parts of tag oligonucleotideswhich are separated from each other. This is illustrated in FIG. 3.

In some embodiments of the invention, a combination of polymerasetranscription and ligational coupling is used. As an example, a gap inan otherwise double stranded nucleic acid can be filled-in by apolymerase and a ligase can ligate the tag portion of the extensionproduct.

Examples of suitable polymerases include DNA polymerase, RNA polymerase,Reverse Transcriptase, DNA ligase, RNA ligase, Taq DNA polymerase, Pfupolymerase, Vent polymerase, HIV-1 Reverse Transcriptase, Klenowfragment, or any other enzyme that will catalyze the incorporation ofcomplementing elements such as mono-, di- or polynucleotides. Othertypes of polymerases that allow mismatch extension could also be used,such for example DNA polymerase η (Washington et al., (2001) JBC 276:2263-2266), DNA polymerase τ (Vaisman et al., (2001) JBC 276:30615-30622), or any other enzyme that allow extension of mismatchedannealed base pairs.

Suitable examples of ligases include Taq DNA ligase, T4 DNA ligase, T4RNA ligase, T7 DNA ligase, and E. coli DNA ligase. The choice of theligase depends, among other things, on the design of the ends to bejoined together. Thus, if the ends are blunt, T4 RNA ligase can bepreferred, while a Taq DNA ligase can be preferred for a sticky endligation, i.e. a ligation in which an overhang on each end is acomplement to each other.

Chemical Reaction Site, Reactants and Reactive Groups

The chemical reaction site can comprise a single reactive group or twoor more reactive groups. In preferred embodiments, the chemical reactionsite comprises 3 or more reactive groups. The plurality of reactivegroups of a chemical reaction site can each react with one or morereactants each comprising one or more reactive groups linked to one ormore chemical entities.

Reactive groups of the chemical reaction site are in principle nodifferent from reactive groups of complementary reactants capable ofreacting with each other under conditions allowing such a reaction tooccur. Examples of reactive groups of chemical reaction sites andcomplementary reactants are listed e.g. in FIG. 58 and in the detaileddisclosure of the invention herein below.

Chemical reaction site reactive groups can be selected a variety of fromwell known reactive groups, such as e.g. hydroxyl groups, thiols,optionally substituted or activated carboxylic acids, isocyanates,amines, esters, thioesters, and the like. Further non-limiting examplesof reactive group reactions are e.g. Suzuki coupling, Heck coupling,Sonogashira coupling, Wittig reaction, alkyl lithium-mediatedcondensations, halogenation, SN2 displacements (for example, N, O, S),ester formation, and amide formation, as well as other reactions andreactive groups that can be used to generate chemical entities, such asthose presented herein.

In general, the chemical reaction site and reactants capable of reactingwith the chemical reaction site, i.e. complementary reactants, can inprinciple be any chemical compounds which are complementary, that is thereactive groups of the entities in question must be able to react.Typically, a reactant can have a single reactive group or more than onereactive group, such as at least two reactive groups, although it ispossible that some of the reactants used will have more than tworeactive groups each. This will be the case when branched molecules aresynthesised.

The number of reactive groups on present on a reactant and/or a chemicalreaction site is suitably from 1 to 10, for example 1, such as 2, forexample 3, such as 4, for example 5, such as 6, for example 7, such as8, for example 9, such as from 2 to 4, for example from 4 to 6, such asfrom 6 to 8, for example from 8 to 10, such as from 2 to 6, for examplefrom 6 to 10, such as from 3 to 6, for example from 6 to 9, such as from4 to 6, for example from 6 to 10 reactive groups present on the chemicalreaction site and/or a reactant capable of reacting with the chemicalreaction site and/or with another reactant.

Reactive groups on two different reactants should be complementary,i.e., capable of reacting to form a covalent bond, optionally with theconcomitant loss of a small molecular entity, such as water, HCl, HF,and so forth.

Two reactive groups are complementary if they are capable of reactingtogether to form a covalent bond. Complementary reactive groups of tworeactants can react, for example, via nucleophilic substitution, to forma covalent bond. In one embodiment, one member of a pair ofcomplementary reactive groups is an electrophilic group and the othermember of the pair is a nucleophilic group. Examples of suitableelectrophilic reactive groups include reactive carbonyl groups, such asacyl chloride groups, ester groups, including carbonylpentafluorophenylesters and succinimide esters, ketone groups and aldehyde groups;reactive sulfonyl groups, such as sulfonyl chloride groups, and reactivephosphonyl groups. Other electrophilic reactive groups include terminalepoxide groups, isocyanate groups and alkyl halide groups. Suitablenucleophilic reactive groups include, but is not limited to, primary andsecondary amino groups and hydroxyl groups and carboxyl groups.

Accordingly, complementary electrophilic and nucleophilic reactivegroups include any two groups which react via nucleophilic substitutionunder suitable conditions to form a covalent bond. A variety of suitablebond-forming reactions are known in the art. See, for example, March,Advanced Organic Chemistry, fourth edition, New York: John Wiley andSons (1992), Chapters 10 to 16; Carey and Sundberg, Advanced OrganicChemistry, Part B, Plenum (1990), Chapters 1-11; and Collman et al.,Principles and Applications of Organotransition Metal Chemistry,University Science Books, Mill Valley, Calif. (1987), Chapters 13 to 20;each of which is incorporated herein by reference in its entirety.

Further suitable complementary reactive groups are set forth hereinbelow. One of skill in the art can readily determine other reactivegroup pairs that can be used in the present method, such as, but notlimited to, reactive groups capable of facilitating the reactionsillustrated in Table 1.

In some embodiments, the reactive groups of the chemical reaction siteand/or the reactive group(s) of one or more reactants reacting with eachother and/or with the chemical reaction site are preferably selectedfrom the group consisting of:

a) activated carboxyl groups, reactive sulfonyl groups and reactivephosphonyl groups, or a combination thereof, and complementary primaryor secondary amino groups; the complementary reactive groups react undersuitable conditions to form amide, sulfonamide and/or phosphonamidatebonds;b) epoxide groups and complementary primary and/or secondary aminogroups; a reactant comprising one or more epoxide reactive group(s) canreact with one or more amine-group(s) of a complementary reactant undersuitable conditions to form one or more carbon-nitrogen bond(s),resulting e.g. in a beta-amino alcohol;c) aziridine groups and complementary primary or secondary amino groups;under suitable conditions, a reactant comprising one or moreaziridine-group(s) can react with one or more amine-group(s) of acomplementary reactant to form one or more carbon-nitrogen bond(s),resulting e.g. in a 1,2-diamine;d) isocyanate groups and complementary primary or secondary aminogroups, a reactant comprising one or more isocyanate-group(s) can reactwith one or more amino-group(s) of a complementary reactant undersuitable conditions to form one or more carbon-nitrogen bond(s),resulting e.g. in a urea group;e) isocyanate groups and complementary hydroxyl groups; a reactantcomprising one or more isocyanate-group(s) can react with acomplementary reactant comprising one or more hydroxyl-groups undersuitable conditions to form one or more carbon-oxygen bond(s), resultinge.g. in a carbamate group.f) amino groups and complementary carbonyl groups; a reactant comprisingone or more amino groups can react with a complementary reactantcomprising one or more carbonyl-group(s), such as aldehyde and/or aketone group(s); the amines can react with such groups via reductiveamination to form e.g. a carbon-nitrogen bond;g) phosphorous ylide groups and complementary aldehyde and/or ketonegroups; A reactant comprising a phosphorus-ylide-group can react with analdehyde and/or a ketone-group of a complementary reactant undersuitable conditions to form e.g. a carbon-carbon double bond, resultinge.g. in an alkene;h) complementary reactive groups can react via cycloaddition to form acyclic structure; an example of such complementary reactive groups arealkynes and organic azides, which can react under suitable conditions toform a triazole ring structure—suitable conditions for such reactionsare known in the art and include those disclosed in WO 03/101972, theentire contents of which are incorporated by reference herein;i) the complementary reactive groups are alkyl halide groups and one ormore nucleophile group(s), such as, but not limited to, nucleophilegroups selected from the group consisting of amino groups, hydroxylgroups and carboxyl group; such groups react under suitable conditionsto form a carbon-nitrogen bond (alkyl halide plus amine) or carbonoxygen bond (alkyl halide plus hydroxyl or carboxyl group);j) the complementary functional groups are halogenated heteroaromaticgroups and one or more nucleophile group(s), the reactants are linkedunder suitable conditions via aromatic nucleophilic substitution;suitable halogenated heteroaromatic groups include chlorinatedpyrimidines, triazines and purines, which react with nucleophiles, suchas amines, under mild conditions in aqueous solution.

As will be clear from the above, a large variety of chemical reactionsmay optionally be used for the formation of one or more covalent bondsbetween a reactant and one or more chemical reaction sites and a largevariety of chemical reactions may optionally be used for the formationof one or more covalent bonds between one or more reactants.

Thus, reactions such as those listed in March's Advanced OrganicChemistry, Organic Reactions, Organic Syntheses, organic text books,journals such as Journal of the American Chemical Society, Journal ofOrganic Chemistry, Tetrahedron, etc., and Carruther's Some ModernMethods of Organic Chemistry can be used. The chosen reactionspreferably are compatible with nucleic acids such as DNA or RNA or arecompatible with the modified nucleic acids used as the template.Reactions useful in stage 1 and stage 2 synthesis include, for example,substitution reactions, carbon-carbon bond forming reactions,elimination reactions, acylation reactions, and addition reactions. Anillustrative but not exhaustive list of aliphatic nucleophilicsubstitution reactions useful in the present invention includes, forexample, SN2 reactions, SNI reactions, SNi reactions, allylicrearrangements, nucleophilic substitution at an aliphatic trigonalcarbon, and nucleophilic substitution at a vinylic carbon. Specificaliphatic nucleophilic substitution reactions with oxygen nucleophilesinclude, for example, hydrolysis of alkyl halides, hydrolysis ofgen-dihalides, hydrolysis of 1,1,1-trihalides, hydrolysis of alkylesters or inorganic acids, hydrolysis of diazo ketones, hydrolysis ofacetal and enol ethers, hydrolysis of epoxides, hydrolysis of acylhalides, hydrolysis of anhydrides, hydrolysis of carboxylic esters,hydrolysis of amides, alkylation with alkyl halides (WilliamsonReaction), epoxide formation, alkylation with inorganic esters,alkylation with diazo compounds, dehydration of alcohols,transetherification, alcoholysis of epoxides, alkylation with oniumsalts, hydroxylation of silanes, alcoholysis of acyl halides,alcoholysis of anhydrides, esterfication of carboxylic acids,alcoholysis of carboxylic esters (transesterfication), alcoholysis ofamides, alkylation of carboxylic acid salts, cleavage of ether withacetic anhydride, alkylation of carboxylic acids with diazo compounds,acylation of carboxylic acids with acyl halides; acylation ofcaripoxylic acids with carboxylic acids, formation of oxoniiim salts,preparation of peroxides and hydroperoxides, preparation of inorganicesters (e.g., nitrites, nitrates, sulfonates), preparation of alcoholsfrom amines, and preparation of mixed organic-inorganic an hydrides.

Specific aliphatic nucleophilic substitution reactions with sulfurnucleophiles, which tend to be better nucleophiles than their oxygenanalogs, include, for example, attack by SH at an alkyl carbon to formthiols, attack by S at an alkyl carbon to form thioethers, attack by SHor SR at an acyl carbon, formation of disulfides, formation of Buntesalts, alkylation of sulfuric acid salts, and formation of alkylthiocyanates.

Aliphatic nucleophilic substitution reactions with nitrogen nucleophilesinclude, for example, alkylation of amines, N-ar[gamma]lation of amines,replacement of a hydroxy by an amino group, transamination,transamidation, alkylation of amines with diazo compounds, animation ofepoxides, amination of oxetanes, amination of aziridines, amination ofalkanes, formation of isocyanides, acylation of amines by acyl halides,acylation of amines by anhydrides, acylation of amines by carboxylicacids, acylation of amines by carboxylic esters, acylation of amines byamides, acylation of amines by other acid derivatives, N-alkylation orN-arylation of amides and imides, N-acylation of amides and imides,formation of aziridines from epoxides, formation of nitro compounds,formation of azides, formation of isocyanates and isothiocyanates, andformation of azoxy compounds. Aliphatic nucleophilic substitutionreactions with halogen nucleophiles include, for example, attack at analkyl carbon, halide exchange, formation of alkyl halides from esters ofsulfuric and sulfonic acids, formation of alkyl halides from alcohols,formation of alkyl halides from ethers, formation of halohydrins fromepoxides, cleavage of carboxylic esters with lithium iodide, conversionof diazo ketones to alpha-halo ketones, conversion of amines to halides,conversion of tertiary amines to cyanamides (the von Braun reaction),formation of acyl halides from carboxylic acids, and formation of acylhalides from acid derivatives.

Aliphatic nucleophilic substitution reactions using hydrogen as anucleophile include, for example, reduction of alkyl halides, reductionof tosylates, other sulfonates, and similar compounds, hydrogenolysis ofalcohols, hydrogenolysis of esters (Barton-McCombie reaction),hydrogenolysis of nitriles, replacement of alkoxyl by hydrogen,reduction of epoxides, reductive cleavage of carboxylic esters,reduction of a C—N bond, desulfurization, reduction of acyl halides,reduction of carboxylic acids, esters, and anhydrides to aldehydes, andreduction of amides to aldehydes.

Although certain carbon nucleophiles may be too nucleophilic and/orbasic to be used in certain embodiments of the invention, aliphaticnucleophilic substitution reactions using carbon nucleophiles include,for example, coupling with silanes, coupling of alkyl halides (the Wurtzreaction), the reaction of alkyl halides and sulfonate esters with GroupI (I A), and II (II A) organometallic reagents, reaction of alkylhalides and sulfonate esters with organocuprates, reaction of alkylhalides and sulfonate esters with other organometallic reagents; allylicand propargylic coupling with a halide substrate, coupling oforganometallic reagents with esters of sulfuric and sulfonic acids,sulfoxides, and sulfones, coupling involving alcohols, coupling oforganometallic reagents with carboxylic esters, coupling oforganometallic reagents with compounds containing an esther linkage,reaction of organometallic reagents with epoxides, reaction oforganometallics with aziridine, alkylation at a carbon bearing an activehydrogen, alkylation of ketones, nitriles, and carboxylic esters,alkylation of carboxylic acid salts, alkylation at a position alpha to aheteroatom (alkylation of 1,3-dithianes), alkylation ofdihydro-1,3-oxazine (the Meyers synthesis of aldehydes, ketones, andcarboxylic acids), alkylation with trialkylboranes, alkylation at analkynyl carbon, preparation of nitriles, direct conversion of alkylhalides to aldehydes and ketones, conversion of alkyl halides, alcohols,or alkanes to carboxylic acids and their derivatives, the conversion ofacyl halides to ketones with organometallic compounds, the conversion ofanhydrides, carboxylic esters, or amides to ketones with organometalliccompounds, the coupling of acyl halides, acylation at a carbon bearingan active hydrogen, acylation of carboxylic esters by carboxylic esters(the Claisen and Dieckmann condensation), acylation of ketones andnitriles with carboxylic esters, acylation of carboxylic acid salts,preparation of acyl cyanides, and preparation of diazo ketones, ketonicdecarboxylation. Reactions which involve nucleophilic attack at asulfonyl sulfur atom may also be used in the present invention andinclude, for example, hydrolysis of sulfonic acid derivatives (attack byOH), formation of sulfonic esters (attack by OR), formation ofsulfonamides (attack by nitrogen), formation of sulfonyl halides (attackby halides), reduction of sulfonyl chlorides (attack by hydrogen), andpreparation of sulfones (attack by carbon).

Aromatic electrophilic substitution reactions may also be used in stage1 and stage 2 synthesis schemes. Hydrogen exchange reactions areexamples of aromatic electrophilic substitution reactions that usehydrogen as the electrophile. Aromatic electrophilic substitution,reactions which use nitrogen electrophiles include, for example,nitration and nitro-dehydrogenation, nitrosation ofnitroso-de-hydrogenation, diazonium coupling, direct introduction of thediazonium group, and amination or amino-dehydrogenation. Reactions ofthis type with sulfur electrophiles include, for example, sulfonation,sulfo-dehydrogenation, halosulfonation, halosulfo-dehydrogenation,sulfurization, and sulfonylation. Reactions using halogen electrophilesinclude, for example, halogenation, and halo-dehydrogenation. Aromaticelectrophilic substitution reactions with carbon electrophiles include,for example, Friedel-Crafts alkylation, alkylation,alkyl-dehydrogenation, Friedel-Crafts arylation (the Scholl reaction),Friedel-Crafts acylation, formylation with disubstituted formamides,formylation with zinc cyanide and HCl (the Gatterman reaction),formylation with chloroform (the Reimer-Tiemami reaction), otherformylations, formyl-dehydrogenation, carboxylation with carbonylhalides, carboxylation with carbon dioxide (the Kolbe-Schmitt reaction),amidation with isocyanates, [Lambda]/-alkylcarbamoyl-dehydrogenation,hydroxyalkylation, hydroxyalkyl-dehydrogenation, cyclodehydration ofaldehydes and ketones, haloalkylation, halo-dehydrogenation,aminoalkylation, amidoalkylation, dialkylaminoalkylation,dialkylamino-dehydrogenation, thioalkylation, acylation with nitriles(the Hoesch reaction), cyanation, and cyano-de hydrogenation. Reactionsusing oxygen electrophiles include, for example, hydroxylation andhydroxy-dehydrogenation.

Rearrangement reactions include, for example, the Fries rearrangement,migration of a nitro group, migration of a nitroso group (theFischer-Hepp Rearrangement), migration of an arylazo group, migration ofa halogen (the Orton rearrangement), migration of an alkyl group, etc.Other reaction on an aromatic ring include the reversal of aFriedel-Crafts alkylation, decarboxylation of aromatic aldehydes,decarboxylation of aromatic acids, the Jacobsen reaction, deoxygenation,desulfonation, hydro-desulfonation, dehalogenation,hydro-dehalogenation, and hydrolysis of organometallic compounds.

Aliphatic electrophilic substitution reactions are also useful.Reactions using the SE1, SE2 (front), SE2 (back), SEi,addition-elimination, and cyclic mechanisms can be used in the presentinvention. Reactions of this type with hydrogen as the leaving groupinclude, for example, hydrogen exchange (deuterio-de-hydrogenation,deuteriation), migration of a double bond, and keto-enoltautomerization. Reactions with halogen electrophiles include, forexample, halogenation of aldehydes and ketones, halogenation ofcarboxylic acids and acyl halides, and halogenation of sulfoxides andsulfones. Reactions with nitrogen electrophiles include, for example,aliphatic diazonium coupling, nitrosation at a carbon bearing an activehydrogen, direct formation of diazo compounds, conversion of amides toalpha-azido amides, direct amination at an activated position, andinsertion by nitrenes. Reactions with sulfur or selenium electrophilesinclude, for example, sulfenylation, sulfonation, and selenylation ofketones and carboxylic esters. Reactions with carbon electrophilesinclude, for example, acylation at an aliphatic carbon, conversion ofaldehydes to beta-keto esters or ketones, cyanation,cyano-de-hydrogenation, alkylation of alkanes, the Stork enaminereaction, and insertion by carbenes. Reactions with metal electrophilesinclude, for example, metalation with organometallic compounds,metalation with metals and strong bases, and conversion of enolates tosilyl enol ethers. Aliphatic electrophilic substitution reactions withmetals as leaving groups include, for example, replacement of metals byhydrogen, reactions between organometallic reagents and oxygen,reactions between organometallic reagents and peroxides, oxidation oftrialkylboranes to borates, conversion of Grignard reagents to sulfurcompounds, halo-demetalation, the conversion of organometallic compoundsto amines, the conversion of organometallic compounds to ketones,aldehydes, carboxylic esters and amides, cyano-de-metalation,transmetalation with a metal, transmetalation with a metal halide,transmetalation with an organometallic compound, reduction of alkylhalides, metallo-de-halogenation, replacement of a halogen by a metalfrom an organometallic compound, decarboxylation of aliphatic acids,cleavage of aikoxides, replacement of a carboxyl group by an acyl group,basic cleavage of beta-keto esters and beta-diketones, haloformreaction, cleavage of non-enolizable ketones, the Haller-Bauer reaction,cleavage of alkanes, decyanation, and hydro-de-cyanation. Electrophilicsubstitution reactions at nitrogen include, for example, diazotization,conversion of hydrazines to azides, N-nitrosation,N-nitroso-de-hydrogenation, conversion of amines to azo compounds,N-halogenation, N-halo-de-hydrogenation, reactions of amines with carbonmonoxide, and reactions of amines with carbon dioxide. Aromaticnucleophilic substitution reactions may also be used in the presentinvention. Reactions proceeding via the SNAr mechanism, the SNImechanism, the benzyne mechanism, the SRN1 mechanism, or othermechanism, for example, can be used. Aromatic nucleophilic substitutionreactions with oxygen nucleophiles include, for example,hydroxy-de-halogenation, alkali fusion of sulfonate salts, andreplacement of OR or OAr. Reactions with sulfur nucleophiles include,for example, replacement by SH or SR. Reactions using nitrogennucleophiles include, for example, replacement by NH2, NHR, or NR2, andreplacement of a hydroxy group by an amino group: Reactions with halogennucleophiles include, for example, the introduction halogens. Aromaticnucleophilic substitution reactions with hydrogen as the nucleophileinclude, for example, reduction of phenols and phenolic esters andethers, and reduction of halides and nitro compounds. Reactions withcarbon nucleophiles include, for example, the Rosenmund-von Braunreaction, coupling of organometallic compounds with aryl halides,ethers, and carboxylic esters, arylation at a carbon containing anactive hydrogen, conversions of aryl substrates to carboxylic acids,their derivatives, aldehydes, and ketones, and the Ullmann reaction.Reactions with hydrogen as the leaving group include, for example,alkylation, arylation, and amination of nitrogen heterocycles. Reactionswith N2<+> as the leaving group include, for example,hydroxy-de-diazoniation, replacement by sulfur-containing groups,iodo-de-diazoniation, and the Schiemann reaction. Rearrangementreactions include, for example, the von Richter rearrangement, theSommelet-Hauser rearrangement, rearrangement of aryl hydroxylamines, andthe Smiles rearrangement. Reactions involving free radicals can also beused, although the free radical reactions used in nucleotide-templatedchemistry should be carefully chosen to avoid modification or cleavageof the nucleotide template. With that limitation, free radicalsubstitution reactions can be used in the present invention. Particularfree radical substitution reactions include, for example, substitutionby halogen, halogenation at an alkyl carbon, allylic halogenation,benzylic halogenation, halogenation of aldehydes, hydroxylation at analiphatic carbon, hydroxylation at an aromatic carbon, oxidation ofaldehydes to carboxylic acids, formation of cyclic ethers, formation ofhydroperoxides, formation of peroxides, acyloxylation,acyloxy-de-hydrogenation, chlorosulfonation, nitration of alkanes,direct conversion of aldehydes to amides, amidation and amination at analkyl carbon, simple coupling at a susceptible position, coupling ofalkynes, arylation of aromatic compounds by diazonium salts, arylationof activated alkenes by diazonium salts (the Meerwein arylation),arylation and alkylation of alkenes by organopalladium compounds (theHeck reaction), arylation and alkylation of alkenes by vinyltincompounds (the StHle reaction), alkylation and arylation of aromaticcompounds by peroxides, photochemical arylation of aromatic compounds,alkylation, acylation, and carbalkoxylation of nitrogen heterocycles.Particular reactions in which N2<+> is the leaving group include, forexample, replacement of the diazonium group by hydrogen, replacement ofthe diazonium group by chlorine or bromine, nitro-de-diazoniation,replacement of the diazonium group by sulfur-containing groups, aryldimerization with diazonium salts, methylation of diazonium salts,vinylation of diazonium salts, arylation of diazonium salts, andconversion of diazonium salts to aldehydes, ketones, or carboxylicacids. Free radical substitution reactions with metals as leaving groupsinclude, for example, coupling of Grignard reagents, coupling ofboranes, and coupling of other organometallic reagents. Reaction withhalogen as the leaving group are included. Other free radicalsubstitution reactions with various leaving groups include, for example,desulfurization with Raney Nickel, conversion of sulfides toorganolithium compounds, decarboxylase dimerization (the Kolbereaction), the Hunsdiecker reaction, decarboxylative allylation, anddecarbonylation of aldehydes and acyl halides.

Reactions involving additions to carbon-carbon multiple bonds are alsoused in the stage 1 and stage 2 synthesis schemes. Any mechanism may beused in the addition reaction including, for example, electrophilicaddition, nucleophilic addition, free radical addition, and cyclicmechanisms. Reactions involving additions to conjugated systems can alsobe used. Addition to cyclopropane rings can also be utilized. Particularreactions include, for example, isomerization, addition of hydrogenhalides, hydration of double bonds, hydration of triple bonds, additionof alcohols, addition of carboxylic acids, addition of H2S and thiols,addition of ammonia and amines, addition of amides, addition ofhydrazoic acid, hydrogenation of double and triple bonds, otherreduction of double and triple bonds, reduction of the double and triplebonds of conjugated systems, hydrogenation of aromatic rings, reductivecleavage of cyclopropanes, hydroboration, other hydrometalations,addition of alkanes, addition of alkenes and/or alkynes to alkenesand/or alkynes (e.g., pi-cation cyclization reactions,hydro-alkenyl-addition), ene reactions, the Michael reaction, additionof organometallics to double and triple bonds not conjugated tocarbonyls, the addition of two alkyl groups to an alkyne, 1,4-additionof organometallic compounds to activated double bonds, addition ofboranes to activated double bonds, addition of tin and mercury hydridesto activated double bonds, acylation of activated double bonds and oftriple bonds, addition of alcohols, amines, carboxylic esters,aldehydes, etc., carbonylation of double and triple bonds,hydrocarboxylation, hydroformylation, addition of aldehydes, addition ofHCN, addition of silanes, radical addition, radical cyclization,halogenation of double and triple bonds (addition of halogen, halogen),halolactonization, halolactamization, addition of hypohalous acids andhypohalites (addition of halogen, oxygen), addition of sulfur compounds(addition of halogen, sulfur), addition of halogen and an amino group(addition of halogen, nitrogen), addition of NOX and NO2X (addition ofhalogen, nitrogen), addition of XN3 (addition of halogen, nitrogen),addition of alkyl halides (addition of halogen, carbon), addition ofacyl halides (addition of halogen, carbon), hydroxylation (addition ofoxygen, oxygen) (e.g., asymmetric dihydroxylation reaction with OSO4),dihydroxylation of aromatic rings, epoxidation (addition of oxygen,oxygen) (e.g., Sharpless asymmetric epoxidation), photooxidation ofdienes (addition of oxygen, oxygen), hydroxysulfenylation (addition ofoxygen, sulfur), oxyamination (addition of oxygen, nitrogen),diamination (addition of nitrogen, nitrogen), formation of aziridines(addition of nitrogen), aminosulferiylation (addition of nitrogen,sulfur), acylacyloxylation and acylamidation (addition of oxygen, carbonor nitrogen, carbon), 1,3-dipolar addition; (addition of oxygen,nitrogen, carbon), Diels-Alder reaction, heteroatom Diels-Alderreaction, all carbon 3+2 cycloadditions, dimerization of alkenes, theaddition of carbenes and carbenoids to double and triple bonds,trimerization and tetramerization of alkynes, and other cycloadditionreactions.

In addition to reactions involving additions to carbon-carbon multiplebonds, addition reactions to carbon-hetero multiple bonds can be used innucleotide-templated chemistry. Exemplary reactions include, forexample, the addition of water to aldehydes and ketones (formation ofhydrates), hydrolysis of carbon-nitrogen double bond, hydrolysis ofaliphatic nitro compounds, hydrolysis of nitriles, addition of alcoholsand thiols to aldehydes and ketones, reductive alkylation of alcohols,addition of alcohols to isocyanates, alcoholysis of nitriles, formationof xanthates, addition of H2S and thiols to carbonyl compounds,formation of bisulfite addition products, addition of amines toaldehydes and ketones, addition of amides to aldehydes, reductivealkylation of ammonia or amines, the Mannich reaction, the addition ofamines to isocyanates, addition of ammonia or amines to nitriles,addition of amines to carbon disulfide and carbon dioxide, addition ofhydrazine derivative to carbonyl compounds, formation of oximes,conversion of aldehydes to nitriles, formation of gem-dihalides fromaldehydes and ketones, reduction of aldehydes and ketones to alcohols,reduction of the carbon-nitrogen double bond, reduction of nitriles toamines, reduction of nitriles to aldehydes, addition of Grignardreagents and organolithium reagents to aldehydes and ketones, additionof other organometallics to aldehydes and ketones, addition oftrialkylallylsilanes to aldehydes and ketones, addition of conjugatedalkenes to aldehydes (the Baylis-Billmah reaction), the Reformatskyreaction, the conversion of carboxylic acid salts to ketones withorganometallic compounds, the addition of Grignard reagents to acidderivatives, the addition of Organometallic compounds to CO2 and CS2,addition of organometallic compounds to C=IM compounds, addition ofcarbenes and diazoalkanbs to C═N compounds, addition of Grignardreagents to nitriles and isocyanates, the Aldol reaction, MukaiyamaAldol and related reactions, Aldol-type reactions between carboxylicesters or amides and aldehydes or ketones, the Knoevenagel reaction(e.g., the Nef reaction, the Favorskii reaction), the Petersonalkenylation reaction, the addition of active hydrogen compounds to CO2and CS2, the Perkin reaction, Darzens glycidic ester condensation, theTollens reaction, the Wittig reaction, the Tebbe alkenylation, thePetasis alkenylation, alternative alkenylations, the Thorpe reaction,the Thorpe-Ziegler reaction, addition of silanes, formation ofcyanohydrins, addition of HCN to C═N and C—N bonds, the Prins reaction,the benzoin condensation, addition of radicals to C═O, C═S, C═Ncompounds, the Ritter reaction, acylation of aldehydes and ketones,addition of aldehydes to aldehydes, the addition of isocyanates toisocyanates (formation of carbodiimides), the conversion of carboxylicacid salts to nitriles, the formation of epoxides from aldehydes andketones, the formation of episulfides and episulfones, the formation ofbeta-lactones and oxetanes (e.g., the Paterno-Buchi reaction), theformation of beta-lactams, etc. Reactions involving addition toisocyanides include the addition of water to isocyanides, the Passerinireaction, the Ug reaction, and the formation of metalated aldimines.Elimination reactions, including alpha, beta, and gamma eliminations, aswell as extrusion reactions, can be performed using nucleotide-templatedchemistry, although the strength of the reagents and conditions employedshould be considered. Preferred elimination reactions include reactionsthat go by EI, E2, EIcB, or E2C mechanisms. Exemplary reactions include,for example, reactions in which hydrogen is removed from one side (e.g.,dehydration of alcohols, cleavage of ethers to alkenes, the Chugaevreaction, ester decomposition, cleavage of quarternary ammoniumhydroxides, cleavage of quaternary ammonium salts with strong bases,cleavage of amine oxides, pyrolysis of keto-ylids, decomposition oftoluene-p-sulfonylhydrazones, cleavage of sulfoxides, cleavage ofselenoxides, cleavage of sulformes, dehydrogalogenation of alkylhalides, dehydrohalogenation of acyl halides, dehydrohalogenation ofsulfonyl halides, elimination of boranes, conversion of alkenes toalkynes, decarbonylation of acyl halides), reactions in which neitherleaving atom is hydrogen (e.g., deoxygenation of vicinal diols, cleavageof cyclic thionocarbonates, conversion of epoxides to episulfides andalkenes, the Ramberg-Backlund reaction, conversion of aziridines toalkenes, dehalogenat[iota]on of vicinal dihalides, dehalogenation ofalpha-halo acyl halides, and elimination of a halogen and a heterogroup), fragmentation reactions (i.e., reactions in which carbon is thepositive leaving group or the electrofuge, such as, for example,fragmentation of gamma-amino and gamma-hydroxy halides, fragmentation of1,3-diols, decarboxylation of beta-hydroxy carboxylic acids,decarboxylation of (3-lactones, fragmentation of alpha-beta-epoxyhydrazones, elimination of CO from bridged bicyclic compounds, andelimination Of CO2 from bridged bicyclic compounds), reactions in whichC═N or C═N bonds are formed (e.g., dehydration of aldoximes or similarcompounds, conversion of ketoximes to nitriles, dehydration ofunsubstituted amides, and conversion of N-alkylformamides toisocyanides), reactions in which C═O bonds are formed (e.g., pyrolysisof beta-hydroxy alkenes), and reactions in which N═N bonds are formed(e.g., eliminations to give diazoalkenes). Extrusion reactions include,for example, extrusion of N2 from pyrazolines, extrusion of N2 frompyrazoles, extrusion of N2 from triazolines, extrusion of CO, extrusionOf CO2, extrusion Of SO2, the Story synthesis, and alkene synthesis bytwofold extrusion.

Rearrangements, including, for example, nucleophilic rearrangements,electrophilic rearrangements, prototropic rearrangements, andfree-radical rearrangements, can also be performed using stage 1 andstage 2 synthesis schemes. Both 1,2 rearrangements and non-1,2rearrangements can be performed. Exemplary reactions include, forexample, carbon-to-carbon migrations of R, H, and Ar (e.g.,Wagner-Meerwein and related reactions, the Pinacol rearrangement, ringexpansion reactions, ring contraction reactions, acid-catalyzedrearrangements of aldehydes and ketones, the dienone-phenolrearrangement, the Favorskii rearrangement, the Arndt-Eistert synthesis,homologation of aldehydes, and homologation of ketones),carbon-to-carbon migrations of other groups (e.g., migrations ofhalogen, hydroxyl, amino, etc.; migration of boron; and the Neberrearrangement), carbon-to-nitrogen migrations of R and Ar (e.g., theHofmann rearrangement, the Curtius rearrangement, the Lossenrearrangement, the Schmidt reaction, the Beckman rearrangement, theStieglits rearrangement, and related rearrangements), carbon-to-oxygenmigrations of R and Ar (e.g., the Baeyer-Villiger rearrangement andrearrangment of hydroperoxides), nitrogen-to-carbon, oxygen-to-carbon,and sulfur-to-carbon migration (e.g., the Stevens rearrangement, and theWittig rearrangement), boron-to-carbon migrations (e.g., conversion ofboranes to alcohols (primary or otherwise), conversion of boranes toaldehydes, conversion of boranes to carboxylic acids, conversion ofvinylic boranes to alkenes, formation of alkynes from boranes andacetylides, formation of alkenes from boranes and acetylides, andformation of ketones from boranes and acetylides), electrocyclicrearrangements (e.g., of cyclobutenes and 1,3-cyclohexadienes, orconversion of stilbenes to phenanthrenes), sigmatropic rearrangements(e.g., (1,j) sigmatropic migrations of hydrogen, (lj) sigmatropicmigrations of carbon, conversion of vinylcyclopropanes to cyclopentenes,the Cope rearrangement, the Claisen rearrangement, the Fischer indolesynthesis, (2,3) sigmatropic rearrangements, and the benzidinerearrangement), other cyclic rearrangements (e.g., metathesis ofalkenes, the di-n-methane and related rearrangements, and theHofmann-Loffler and related reactions), and non-cyclic rearrangements(e.g., hydride shifts, the Chapman rearrangement, the Wallachrearrangement, and dybtropic rearrangements). Oxidative and reductivereactions may also be performed using stage 1 and stage 2 synthesisschemes. Exemplary reactions may involve, for example, direct electrontransfer, hydride transfer, hydrogen-atom transfer, formation of esterintermediates, displacement mechanisms, or addition-eliminationmechanisms. Exemplary oxidations include, for example, eliminations ofhydrogen (e.g., aromatization of six-membered rings, dehydrogenationsyielding carbon-carbon double bonds, oxidation or dehydrogenation ofalcohols to aldehydes and ketones, oxidation of phenols and aromaticamines to quinones, oxidative cleavage of ketones, oxidative cleavage ofaldehydes, oxidative cleavage of alcohols, ozonolysis, oxidativecleavage of double bonds and aromatic rings, oxidation of aromatic sidechains, oxidative decarboxylation, and bisdecarboxylation), reactionsinvolving replacement of hydrogen by oxygen (e.g., oxidation ofmethylene to carbonyl, oxidation of methylene to OH, CO2R, or OR,oxidation of arylmethanes, oxidation of ethers to carboxylic esters andrelated reactions, oxidation of aromatic hydrocarbons to quinones,oxidation of amines or nitro compounds to aldehydes, ketones, ordihalides, oxidation of primary alcohols to carboxylic acids orcarboxylic esters, oxidation of alkenes to aldehydes or ketones,oxidation of amines to nitroso compounds and hydroxylamines, oxidationof primary amines, oximes, azides, isocyanates, or nitroso compounds, tonitro compounds, oxidation of thiols and other sulfur compounds tosulfonic acids), reactions in which oxygen is added to the substrate(e.g., oxidation of alkynes to alpha-diketones, oxidation of tertiaryamines to amine oxides, oxidation of thioesters to sulfoxides andsulfones, and oxidation of carboxylic acids to peroxy acids, andoxidative coupling reactions (e.g., coupling involving carbanoins,dimerization of silyl enol ethers or of lithium enolates, and oxidationof thiols to disulfides).

Exemplary reductive reactions include, for example, reactions involvingreplacement of oxygen by hydrogen {e.g., reduction of carbonyl tomethylene in aldehydes and ketones, reduction of carboxylic acids toalcohols, reduction of amides to amines, reduction of carboxylic estersto ethers, reduction of cyclic anhydrides to lactones and acidderivatives to alcohols, reduction of carboxylic esters to alcohols,reduction of carboxylic acids and esters to alkanes, complete reductionof epoxides, reduction of nitro compounds to amines, reduction of nitrocompounds to hydroxylamines, reduction of nitroso compounds andhydroxylamines to amines, reduction of oximes to primary amines oraziridines, reduction of azides to primary amines, reduction of nitrogencompounds, and reduction of sulfonyl halides and sulfonic acids tothiols), removal of oxygen from the substrate {e.g., reduction of amineoxides and azoxy compounds, reduction of sulfoxides and sulfones,reduction of hydroperoxides and peroxides, and reduction of aliphaticnitro compounds to oximes or nitrites), reductions that include cleavage{e.g., de-alkylation of amines and amides, reduction of azo, azoxy, andhydrazo compounds to amines, and reduction of disulfides to thiols),reductive coupling reactions {e.g., bimolecular reduction of aldehydesand ketones to 1,2-diols, bimolecular reduction of aldehydes or ketonesto alkenes, acyloin ester condensation, reduction of nitro to azoxycompounds, and reduction of nitro to azo compounds), and. reductions inwhich an organic substrate is both oxidized and reduced {e.g., theCannizzaro reaction, the Tishchenko reaction, the Pummererrearrangement, and the Willgerodt reaction).

In one embodiment, a reactive group may comprise a nitrogen atom such asfor example an amine, an isocyanate, an isocyanide, a hydroxylamine, ahydrazine, a nitrile, an amide, a lactam, an imine, an azo group, anitro group, a nitroso group, an amidine group, a guanidine group, acarbamate, an azide, which may optionally be substituted by one or moresubstituents depending on the type of reactive group. In one embodiment,a reactive group may comprise an oxygen atom such as for example ahydroxyl group, an ether, a ketone, an aldehyde, a hemiacetal, ahemiketal, an acetal, a ketal, a carboxylic acid, a carboxylic acidester, an ortho ester, a carbonate, a carbamate, a lactam, a lactone, ahydroxylamine, which may optionally be substituted by one or moresubstituents depending on the type of reactive group.

In one embodiment, a reactive group may comprise a sulfur atom such asfor example a thiol, a disulfide, a sulfide, a sulfoxide, a sulfinamide, a sulfonamide, a sulfone, a sultam, a sultone, a thioketone, athioaldehyde, a dithioacetal, a carboxylic acid thioester, athiocarbonate, a thiocarbamate, a isothiocyanate, which may optionallybe substituted by one or more substituents depending on the type ofreactive group.

In one embodiment, a reactive group may comprise a halogen such as forexample fluorine, chlorine, bromine, iodine, for example alkylchloride,alkylbromide, alkyliodide, alkenylchloride, alkenylbromide,alkenyliodide, alkynylchloride, alkynylbromide, alkynyliodide,arylfluoride, arylchloride, arylbromide, aryliodide, hetarylfluoride,hetarylchloride, hetarylbromide, hetaryliodide, carbonylfluoride,carbonylchloride, carbonylbromide, carbonyliodide, sulfonylfluoride,sulfonylchloride, sulfonylbromide, sulfonyliodide, which may optionallybe substituted by one or more substituents depending on the type ofreactive group.

In one embodiment, a reactive group may comprise a carbon atom such asfor example an alkene, an alpha,beta-unsaturated ketone, analpha,beta-unsaturated aldehyde, an alpha,beta-unsaturated carboxylicacid ester, an alpha,beta-unsaturated carboxylic acid amide, analpha,beta-unsaturated sulfoxide, an alpha,beta-unsaturated sulfone, analpha,beta-unsaturated sulfonamide, an alpha,beta-unsaturatedsulfonylchloride, a nitro alkene, such as a vinylogous nitro group(alpha,beta-unsaturated nitroalkene), an alkyne, an arene, a hetarene, anitrile, an amide, a lactam, an imine, a nitroalkyl group, a nitroarylgroup, an amidine group, a carbamate, a ketone, an aldehyde, ahemiacetal, a hemiketal, an acetal, a ketal, a carboxylic acid, acarboxylic acid ester, an ortho ester, a carbonate, a carbamate, alactam, a lactone, a carbosulfone, a carbosultam, a carbosultone, athioketone, a thioaldehyde, a dithioacetal, a carboxylic acid thioester,a thiocarbonate, a thiocarbamate, an alkylchloride, an alkylbromide, analkyliodide, an alkenylchloride, an alkenylbromide, an alkenyliodide, analkynylchloride, an alkynylbromide, an alkynyliodide, an arylfluoride,an arylchloride, an arylbromide, an aryliodide, an hetarylfluoride, anhetarylchloride, an hetarylbromide, an hetaryliodide, ancarbonylfluoride, an carbonylchloride, an carbonylbromide, ancarbonyliodide, an isocyanate, an isothiocyanate, an isocyanide, aalkylphosphonium group such as for example alkyltriphenylphosphoniumchloride, for example alkyltriphenylphosphonium bromide, for examplealkyltriphenylphosphonium iodide, which may optionally be substituted byone or more substituents depending on the type of reactive group.

Reactive groups may also comprising further functional groups asdescribed in Comprehensive Organic Functional Group Transformations,Eds. A. R. Katritsky, O. Meth-Cohn, C. W. Rees, Pergamon, Elsevier 1995Volumes 1-6, which are hereby incorporated by reference.

A chemical reactive site may comprise one or more reactive groups forexample chemical reactive sites comprising 1-10 reactive groups, forexample one reactive group, for example two reactive groups, for examplethree reactive groups, for example four reactive groups, for examplefive reactive groups.

A reactant may comprise one or more reactive groups for examplereactants comprising 1-10 reactive groups, for example one reactivegroup, for example two reactive groups, for example three reactivegroups, for example four reactive groups, for example five reactivegroups.

In one embodiment, a reactant comprises two reactive groups, such as forexample a diamine, an aminoketone, an aminoalcohol, an aminothiol, anaminoacid, such as for example an amino carboxylic acid, an aminoacidester such as for example and amino carboxylic acid ester, an aminoacidamide such as for example an amino carboxylic acid amide, an aminochloroazine such as for example an amino chloropyridine, for example anamino chloropyrimidine, an amino chloropyridazine, an aminochloropyrazine, an amino fluoroazine such as for example an aminofluoropyridin, for example an amino fluoropyrimidine, an aminofluoropyridazine, an amino fluoro pyrazine, an Fmoc protected diamine,an Fmoc protected aminoketone, an Fmoc protected aminoalcohol, an Fmocprotected aminoacid such as for example an Fmoc protected aminocarboxylic acid, an Fmoc protected aminoacid ester such as for examplean Fmoc protected amino carboxylic acid ester, an Fmoc protectedaminoacid amide such as for example an Fmoc protected amino carboxylicacid amide, an Fmoc protected aminoisocyanate, an Fmoc protected aminochloroazine such as for example an Fmoc protected amino chloropyridine,for example an Fmoc protected amino chloropyrimidine, an Fmoc protectedamino chloropyridazine, an Fmoc protected amino chloropyrazine, an Fmocprotected amino fluoroazine such as for example an Fmoc protected aminofluoropyridin, for example an Fmoc protected amino fluoropyrimidine, anFmoc protected amino fluoropyridazine, an Fmoc protected amino fluoropyrazine, an Fmoc protected aminosulfonylchloride, an Fmoc protectedaminoaldehyde, an Fmoc protected aminoisocyanate, an MSc protecteddiamine, an MSc protected aminoketone, an MSc protected aminoalcohol, anMSc protected aminoacid, an MSc protected aminoacid such as for examplean MSc protected amino carboxylic acid, an MSc protected aminoacid estersuch as for example an MSc protected amino carboxylic acid ester, an MScprotected aminoacid amide such as for example an MSc protected aminocarboxylic acid amide, an MSc protected aminoisocyanate, an MScprotected amino chloroazine such as for example an MSc protected aminochloropyridine, for example an MSc protected amino chloropyrimidine, anMSc protected amino chloropyridazine, an MSc protected aminochloropyrazine, an MSc protected amino fluoroazine such as for examplean MSc protected amino fluoropyridin, for example an MSc protected aminofluoropyrimidine, an MSc protected amino fluoropyridazine, an MScprotected amino fluoro pyrazine, an MSc protected aminosulfonylchloride,an MSc protected aminoaldehyde, an MSc protected aminoisocyanate, a4-pentenoyl protected diamine, a 4-pentenoyl protected aminoketone, a4-pentenoyl protected aminoalcohol, a 4-pentenoyl protected aminoacidsuch as for example a 4-pentenoyl protected amino carboxylic acid, a4-pentenoyl protected aminoacid ester such as for example a 4-pentenoylprotected amino carboxylic acid ester, a 4-pentenoyl protected aminoacidamide such as for example a 4-pentenoyl protected amino carboxylic acidamide, a 4-pentenoyl protected aminoisocyanate, a 4-pentenoyl protectedamino chloroazine such as for example a 4-pentenoyl protected aminochloropyridine, for example an 4-pentenoyl protected aminochloropyrimidine, a 4-pentenoyl protected amino chloropyridazine, a4-pentenoyl protected amino chloropyrazine, a 4-pentenoyl protectedamino fluoroazine such as for example a 4-pentenoyl protected aminofluoropyridin, for example a 4-pentenoyl protected aminofluoropyrimidine, a 4-pentenoyl protected amino fluoropyridazine, a4-pentenoyl protected amino fluoro pyrazine, a 4-pentenoyl protectedaminosulfonylchloride, a 4-pentenoyl protected aminoaldehyde, a4-pentenoyl protected aminoisocyanate, a Boc protected diamine, a Bocprotected aminoketone, a Boc protected aminoalcohol, a Boc protectedaminoacid such as for example a Boc protected amino carboxylic acid, aBoc protected aminoacid ester such as for example a Boc protected aminocarboxylic acid ester, a Boc protected aminoacid amide such as forexample a Boc protected amino carboxylic acid amide, a Boc protectedaminoisocyanate, a Boc protected amino chloroazine such as for examplean Boc protected amino chloropyridine, for example a Boc protected aminochloropyrimidine, a Boc protected amino chloropyridazine, a Bocprotected amino chloropyrazine, a Boc protected amino fluoroazine suchas for example a Boc protected amino fluoropyridin, for example an Bocprotected amino fluoropyrimidine, an Boc protected aminofluoropyridazine, an Boc protected amino fluoro pyrazine, a o-Nsprotected diamine, a o-Ns protected aminoketone, a o-Ns protectedaminoalcohol, a o-Ns protected aminoacid such as for example a o-Nsprotected amino carboxylic acid, a o-Ns protected aminoacid ester suchas for example a o-Ns protected amino carboxylic acid ester, a o-Nsprotected aminoacid amide such as for example a o-Ns protected aminocarboxylic acid amide, a o-Ns protected aminoisocyanate, a o-Nsprotected amino chloroazine such as for example an o-Ns protected aminochloropyridine, for example a o-Ns protected amino chloropyrimidine, ao-Ns protected amino chloropyridazine, a o-Ns protected aminochloropyrazine, a o-Ns protected amino fluoroazine such as for example ao-Ns protected amino fluoropyridin, for example an o-Ns protected aminofluoropyrimidine, an o-Ns protected amino fluoropyridazine, an o-Nsprotected amino fluoro pyrazine, a p-Ns protected diamine, a p-Nsprotected aminoketone, a p-Ns protected aminoalcohol, a p-Ns protectedaminoacid such as for example a p-Ns protected amino carboxylic acid, ap-Ns protected aminoacid ester such as for example a p-Ns protectedamino carboxylic acid ester, a p-Ns protected aminoacid amide such asfor example a p-Ns protected amino carboxylic acid amide, a p-Nsprotected aminoisocyanate, a p-Ns protected amino chloroazine such asfor example an p-Ns protected amino chloropyridine, for example a p-Nsprotected amino chloropyrimidine, a p-Ns protected aminochloropyridazine, a p-Ns protected amino chloropyrazine, a p-Nsprotected amino fluoroazine such as for example a p-Ns protected aminofluoropyridin, for example an p-Ns protected amino fluoropyrimidine, anp-Ns protected amino fluoropyridazine, an p-Ns protected amino fluoropyrazine, a allyl carbamate protected diamine, a allyl carbamateprotected aminoketone, a allyl carbamate protected aminoalcohol, a allylcarbamate protected aminoacid such as for example a allyl carbamateprotected amino carboxylic acid, a allyl carbamate protected aminoacidester such as for example a allyl carbamate protected amino carboxylicacid ester, a allyl carbamate protected aminoacid amide such as forexample a allyl carbamate protected amino carboxylic acid amide, a allylcarbamate protected aminoisocyanate, a allyl carbamate protected aminochloroazine such as for example an allyl carbamate protected aminochloropyridine, for example a allyl carbamate protected aminochloropyrimidine, a allyl carbamate protected amino chloropyridazine, aallyl carbamate protected amino chloropyrazine, a allyl carbamateprotected amino fluoroazine such as for example a allyl carbamateprotected amino fluoropyridin, for example an allyl carbamate protectedamino fluoropyrimidine, an allyl carbamate protected aminofluoropyridazine, an allyl carbamate protected amino fluoro pyrazine, abenzyl carbamate protected diamine, a benzyl carbamate protectedaminoketone, a benzyl carbamate protected aminoalcohol, a benzylcarbamate protected aminoacid such as for example a benzyl carbamateprotected amino carboxylic acid, a benzyl carbamate protected aminoacidester such as for example a benzyl carbamate protected amino carboxylicacid ester, a benzyl carbamate protected aminoacid amide such as forexample a benzyl carbamate protected amino carboxylic acid amide, abenzyl carbamate protected aminoisocyanate, a benzyl carbamate protectedamino chloroazine such as for example an benzyl carbamate protectedamino chloropyridine, for example a benzyl carbamate protected aminochloropyrimidine, a benzyl carbamate protected amino chloropyridazine, abenzyl carbamate protected amino chloropyrazine, a benzyl carbamateprotected amino fluoroazine such as for example a benzyl carbamateprotected amino fluoropyridin, for example an benzyl carbamate protectedamino fluoropyrimidine, an benzyl carbamate protected aminofluoropyridazine, an benzyl carbamate protected amino fluoro pyrazine, aFmoc protected aminofluorotriazine such as for example a Fmoc protectedaminofluoro-1,2,3-triazine, for example a Fmoc protectedaminofluoro-1,2,4-triazine, for example a Fmoc protectedaminofluoro-1,3,5-triazine, a Fmoc protected aminochlorotriazine such asfor example a Fmoc protected aminochloro-1,2,3-triazine, for example aFmoc protected aminochloro-1,2,4-triazine, for example a Fmoc protectedaminochloro-1,3,5-triazine, a MSc protected aminofluorotriazine such asfor example a MSc protected aminofluoro-1,2,3-triazine, for example aMSc protected aminofluoro-1,2,4-triazine, for example a MSc protectedaminofluoro-1,3,5-triazine, a MSc protected aminochlorotriazine such asfor example a MSc protected aminochloro-1,2,3-triazine, for example aMSc protected aminochloro-1,2,4-triazine, for example a MSc protectedaminochloro-1,3,5-triazine, a o-Ns protected aminofluorotriazine such asfor example a o-Ns protected aminofluoro-1,2,3-triazine, for example ao-Ns protected aminofluoro-1,2,4-triazine, for example a o-Ns protectedaminofluoro-1,3,5-triazine, a o-Ns protected aminochlorotriazine such asfor example a o-Ns protected aminochloro-1,2,3-triazine, for example ao-Ns protected aminochloro-1,2,4-triazine, for example a o-Ns protectedaminochloro-1,3,5-triazine, a p-Ns protected aminofluorotriazine such asfor example a p-Ns protected aminofluoro-1,2,3-triazine, for example ap-Ns protected aminofluoro-1,2,4-triazine, for example a p-Ns protectedaminofluoro-1,3,5-triazine, a p-Ns protected aminochlorotriazine such asfor example a p-Ns protected aminochloro-1,2,3-triazine, for example ap-Ns protected aminochloro-1,2,4-triazine, for example a p-Ns protectedaminochloro-1,3,5-triazine, a allyl carbamate protectedaminofluorotriazine such as for example a allyl carbamate protectedaminofluoro-1,2,3-triazine, for example a allyl carbamate protectedaminofluoro-1,2,4-triazine, for example a allyl carbamate protectedaminofluoro-1,3,5-triazine, a allyl carbamate protectedaminochlorotriazine such as for example a allyl carbamate protectedaminochloro-1,2,3-triazine, for example a allyl carbamate protectedaminochloro-1,2,4-triazine, for example a allyl carbamate protectedaminochloro-1,3,5-triazine, a benzyl carbamate protectedaminofluorotriazine such as for example a benzyl carbamate protectedaminofluoro-1,2,3-triazine, for example a benzyl carbamate protectedaminofluoro-1,2,4-triazine, for example a benzyl carbamate protectedaminofluoro-1,3,5-triazine, a benzyl carbamate protectedaminochlorotriazine such as for example a benzyl carbamate protectedaminochloro-1,2,3-triazine, for example a benzyl carbamate protectedaminochloro-1,2,4-triazine, for example a benzyl carbamate protectedaminochloro-1,3,5-triazine, wherein such reactive groups may optionallybe protected by protection groups, for example amino protection groupssuch as for example Fmoc, for example MSc, for example Boc, for example4-pentenoyl, for example o-Ns, for example p-Ns, for example allylcarbamate, for example benzyl carbamate and a combination thereof, forexample carboxylic acid protection such as methyl ester, ethyl ester,t-butyl ester, 2,2,2-trichloroethyl ester, benzyl ester, p-methoxybenzyl ester, o-nitrobenzyl ester, methylsulfonylethyl ester, forexample aldehyde protection such as an acetal or the aldehyde mayoptionally be masked as a 1,2-diol and a combination thereof, whereinsuch reactants may optionally be substituted by one or moresubstituents.

In a further embodiment, a reactant comprises two reactive groups, suchas for example a mercaptoaldehyde, a hydroxyaldehyde, a formylalkylcarboxylic acid, a formyl aryl carboxylic acid, a formyl hetarylcarboxylic acid, a formyl alkylaryl carboxylic acid, a formylalkylhetaryl carboxylic acid, a formyl arylalkyl carboxylic acid, aformyl hetarylalkyl carboxylic acid, a formylalkyl carboxylic acidester, a formyl aryl carboxylic acid ester, a formyl hetaryl carboxylicacid ester, a formyl alkylaryl carboxylic acid ester, a formylalkylhetaryl carboxylic acid ester, a formyl arylalkyl carboxylic acidester, a formyl hetarylalkyl carboxylic acid ester, a formylalkylsulfonyl chloride, a formyl aryl sulfonyl chloride, a formyl hetarylsulfonyl chloride, a formyl alkylaryl sulfonyl chloride, a formylalkylhetaryl sulfonyl chloride, a formyl arylalkyl sulfonyl chloride, aformyl hetarylalkyl sulfonyl chloride, a formylalkyl isocyanate, aformyl aryl isocyanate, a formyl hetaryl isocyanate, a formyl alkylarylisocyanate, a formyl alkylhetaryl isocyanate, a formyl arylalkylisocyanate, a formyl hetarylalkyl isocyanate, a formylalkyl isocyanide,a formyl aryl isocyanide, a formyl hetaryl isocyanide, a formylalkylaryl isocyanide, a formyl alkylhetaryl isocyanide, a formylarylalkyl isocyanide, a formyl hetarylalkyl isocyanide, a formylchloroazine such as for example a formyl chloropyridine, for example aformyl chloropyrimidine, a formyl chloropyridazine, a formylchloropyrazine, a formyl fluoroazine such as for example a formylfluoropyridin, for example a formyl fluoropyrimidine, a formylfluoropyridazine, a formyl fluoro pyrazine, a formyl fluorotriazine, aformylchlorotriazine, wherein such reactive groups may optionally beprotected by protection groups, for example amino protection groups suchas for example Fmoc, for example MSc, for example Boc, for example4-pentenoyl, for example o-Ns, for example p-Ns, for example allylcarbamate, for example benzyl carbamate and a combination thereof, forexample carboxylic acid protection such as methyl ester, ethyl ester,t-butyl ester, 2,2,2-trichloroethyl ester, benzyl ester, p-methoxybenzyl ester, o-nitrobenzyl ester, methylsulfonylethyl ester, forexample aldehyde protection such as an acetal or the aldehyde mayoptionally be masked as a 1,2-diol and a combination thereof, whereinsuch reactants may optionally be substituted by one or moresubstituents.

In a further embodiment, a reactant comprises two reactive groups, suchas for example a dicarboxylic acid, a alkoxycarbonylalkyl carboxylicacid, a alkoxycarbonyl aryl carboxylic acid, a alkoxycarbonyl hetarylcarboxylic acid, a alkoxycarbonyl alkylaryl carboxylic acid, aalkoxycarbonyl alkylhetaryl carboxylic acid, a alkoxycarbonyl arylalkylcarboxylic acid, a alkoxycarbonyl hetarylalkyl carboxylic acid, acarboxyalkyl sulfonyl chloride, a carboxy aryl sulfonyl chloride, acarboxy hetaryl sulfonyl chloride, a carboxy alkylaryl sulfonylchloride, a carboxy alkylhetaryl sulfonyl chloride, a carboxy arylalkylsulfonyl chloride, a carboxy hetarylalkyl sulfonyl chloride, aalkoxycarbonylalkyl sulfonyl chloride, a alkoxycarbonyl aryl sulfonylchloride, a alkoxycarbonyl hetaryl sulfonyl chloride, a alkoxycarbonylalkylaryl sulfonyl chloride, a alkoxycarbonyl alkylhetaryl sulfonylchloride, a alkoxycarbonyl arylalkyl sulfonyl chloride, a alkoxycarbonylhetarylalkyl sulfonyl chloride, a alkoxycarbonylalkyl isocyanate, aalkoxycarbonyl aryl isocyanate, a alkoxycarbonyl hetaryl isocyanate, aalkoxycarbonyl alkylaryl isocyanate, a alkoxycarbonyl alkylhetarylisocyanate, a alkoxycarbonyl arylalkyl isocyanate, a alkoxycarbonylhetarylalkyl isocyanate, a alkoxycarbonyl chloroazine such as forexample a alkoxycarbonyl chloropyridine, for example a alkoxycarbonylchloropyrimidine, a alkoxycarbonyl chloropyridazine, a alkoxycarbonylchloropyrazine, a alkoxycarbonyl fluoroazine such as for example aalkoxycarbonyl fluoropyridin, for example a alkoxycarbonylfluoropyrimidine, a alkoxycarbonyl fluoropyridazine, a alkoxycarbonylfluoro pyrazine, a alkoxycarbonyl fluorotriazine, aalkoxycarbonylchlorotriazine, a carboxycarbonyl chloroazine such as forexample a carboxycarbonyl chloropyridine, for example a carboxycarbonylchloropyrimidine, a carboxycarbonyl chloropyridazine, a carboxycarbonylchloropyrazine, a carboxycarbonyl fluoroazine such as for example acarboxycarbonyl fluoropyridin, for example a carboxycarbonylfluoropyrimidine, a carboxycarbonyl fluoropyridazine, a carboxycarbonylfluoro pyrazine, a carboxycarbonyl fluorotriazine, acarboxycarbonylchlorotriazine, a chlorosulfonyl chloroazine such as forexample a chlorosulfonyl chloropyridine, for example a chlorosulfonylchloropyrimidine, a chlorosulfonyl chloropyridazine, a chlorosulfonylchloropyrazine, a chlorosulfonyl fluoroazine such as for example achlorosulfonyl fluoropyridin, for example a chlorosulfonylfluoropyrimidine, a chlorosulfonyl fluoropyridazine, a chlorosulfonylfluoro pyrazine, a chlorosulfonyl fluorotriazine, achlorosulfonylchlorotriazine, a dihaloazine such as for example adihalopyridin, for example a dihalopyrimidine, a dihalopyridazine, adihalo pyrazine, a dihalotriazine, a dihalotriazine such as for examplea dihalo-1,2,3-triazine, for example a dihalo-1,2,4-triazine, forexample a dihalo-1,3,5-triazine, a dichloroazine such as for example adichloropyridin, for example a dichloropyrimidine, a dichloropyridazine,a dichloro pyrazine, a dichlorotriazine, a dichlorotriazine such as forexample a dichloro-1,2,3-triazine, for example adichloro-1,2,4-triazine, for example a dichloro-1,3,5-triazine, adifluoroazine such as for example a difluoropyridin, for example adifluoropyrimidine, a difluoropyridazine, a difluoropyrazine, adifluorotriazine, a difluorotriazine such as for example adifluoro-1,2,3-triazine, for example a difluoro-1,2,4-triazine, forexample a difluoro-1,3,5-triazine, a chlorofluoroazine such as forexample a chlorofluoropyridin, for example a chlorofluoropyrimidine, achlorofluoropyridazine, a chlorofluoro pyrazine, a chlorofluorotriazine,a chlorofluorotriazine such as for example achlorofluoro-1,2,3-triazine, for example a chlorofluoro-1,2,4-triazine,for example a chlorofluoro-1,3,5-triazine, wherein such reactive groupsmay optionally be protected by further protection groups, for examplecarboxylic acid protection such as methyl ester, ethyl ester, t-butylester, 2,2,2-trichloroethyl ester, methylsulfonylethyl ester, benzylester, p-methoxy benzyl ester, o-nitrobenzyl ester, wherein suchreactive groups may optionally be protected by protection groups, forexample amino protection groups such as for example Fmoc, for exampleMSc, for example Boc, for example 4-pentenoyl, for example o-Ns, forexample p-Ns, for example allyl carbamate, for example benzyl carbamateand a combination thereof, for example carboxylic acid protection suchas methyl ester, ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester,benzyl ester, p-methoxy benzyl ester, o-nitrobenzyl ester,methylsulfonylethyl ester, for example aldehyde protection such as anacetal or the aldehyde may optionally be masked as a 1,2-diol and acombination thereof, wherein such reactants may optionally besubstituted by one or more substituents.

In a further embodiment, a reactant comprises two reactive groups, suchas for example an alpha,beta-unsaturated aldehyde, analpha,beta-unsaturated sulfonyl chloride, an alpha,beta-unsaturatedcarboxylic acid, an alpha,beta-unsaturated carboxylic acid ester, analpha,beta-unsaturated isocyanate, an alpha,beta-unsaturated ketone,wherein such reactive groups may optionally be protected by protectiongroups, for example amino protection groups such as for example Fmoc,for example MSc, for example Boc, for example 4-pentenoyl, for exampleo-Ns, for example p-Ns, for example allyl carbamate, for example benzylcarbamate and a combination thereof, for example carboxylic acidprotection such as methyl ester, ethyl ester, t-butyl ester,2,2,2-trichloroethyl ester, benzyl ester, p-methoxy benzyl ester,o-nitrobenzyl ester, methylsulfonylethyl ester, for example aldehydeprotection such as an acetal or the aldehyde may optionally be masked asa 1,2-diol and a combination thereof, wherein such reactants mayoptionally be substituted by one or more substituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example a triamine, a diamino carboxylic acid, an aminodicarboxylic acid, a tricarboxylic acid, wherein such reactive groupsmay optionally be protected by protection groups, for example aminoprotection groups such as for example Fmoc, for example MSc, for exampleBoc, for example 4-pentenoyl, for example o-Ns, for example p-Ns, forexample allyl carbamate, for example benzyl carbamate and a combinationthereof, for example carboxylic acid protection such as methyl ester,ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester, benzyl ester,p-methoxy benzyl ester, o-nitrobenzyl ester, methylsulfonylethyl ester,for example aldehyde protection such as an acetal or the aldehyde mayoptionally be masked as a 1,2-diol and a combination thereof, whereinsuch reactants may optionally be substituted by one or moresubstituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example trihalotriazine for example trichlorotriazine,trifluorotriazine, dichlorofluorotriazine, difluorochlorotriazine, suchas for example formyl dihaloazines, carboxy dihaloazines, chlorosulfonyldihaloazines, isocyanato dihaloazines, amino dihaloazines,trihaloazinylazine, dihaloazinylhaloazine, wherein such reactive groupsmay optionally be protected by protection groups, for example aminoprotection groups such as for example Fmoc, for example MSc, for exampleBoc, for example 4-pentenoyl, for example o-Ns, for example p-Ns, forexample allyl carbamate, for example benzyl carbamate and a combinationthereof, for example carboxylic acid protection such as methyl ester,ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester, benzyl ester,p-methoxy benzyl ester, o-nitrobenzyl ester, methylsulfonylethyl ester,for example aldehyde protection such as an acetal or the aldehyde mayoptionally be masked as a 1,2-diol and a combination thereof, whereinsuch reactants may optionally be substituted by one or moresubstituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example a diamino aldehyde, an amino dialdehyde, atrialdehyde, wherein such reactive groups may optionally be protected byprotection groups, for example amino protection groups such as forexample Fmoc, for example MSc, for example Boc, for example 4-pentenoyl,for example o-Ns, for example p-Ns, for example allyl carbamate, forexample benzyl carbamate and a combination thereof, for examplecarboxylic acid protection such as methyl ester, ethyl ester, t-butylester, 2,2,2-trichloroethyl ester, benzyl ester, p-methoxy benzyl ester,o-nitrobenzyl ester, methylsulfonylethyl ester, for example aldehydeprotection such as an acetal or the aldehyde may optionally be masked asa 1,2-diol and a combination thereof, wherein such reactants mayoptionally be substituted by one or more substituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example a diformyl carboxylic acid, a formyl dicarboxylicacid, a formyl amino carboxylic acid, wherein such reactive groups mayoptionally be protected by protection groups, for example aminoprotection groups such as for example Fmoc, for example MSc, for exampleBoc, for example 4-pentenoyl, for example o-Ns, for example p-Ns, forexample allyl carbamate, for example benzyl carbamate and a combinationthereof, for example carboxylic acid protection such as methyl ester,ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester, benzyl ester,p-methoxy benzyl ester, o-nitrobenzyl ester, methylsulfonylethyl ester,for example aldehyde protection such as an acetal or the aldehyde mayoptionally be masked as a 1,2-diol and a combination thereof, whereinsuch reactants may optionally be substituted by one or moresubstituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example an alpha,beta-unsaturated aminoaldehyde, analpha,beta-unsaturated aminosulfonyl chloride, an alpha,beta-unsaturatedaminocarboxylic acid, an alpha,beta-unsaturated aminocarboxylic acidester, an alpha,beta-unsaturated aminoisocyanate, analpha,beta-unsaturated aminoketone, an alpha,beta-unsaturatedaminocarboxylic acid amide, an alpha,beta-unsaturated aminosulfoxide, analpha,beta-unsaturated aminosulfone, an alpha, beta-unsaturatedaminosulfonamide, an alpha,beta-unsaturated aminosulfonylchloride, anitro aminoalkene, such as comprising a vinylogous nitro group(alpha,beta-unsaturated nitroaminoalkene), an alpha,beta-unsaturatedformylaldehyde, an alpha,beta-unsaturated formylsulfonyl chloride, analpha,beta-unsaturated formylcarboxylic acid, an alpha,beta-unsaturatedformylcarboxylic acid ester, an alpha,beta-unsaturated formylisocyanate,an alpha, beta-unsaturated formylketone, an alpha,beta-unsaturatedformylcarboxylic acid amide, an alpha,beta-unsaturated formylsulfoxide,an alpha, beta-unsaturated formylsulfone, an alpha, beta-unsaturatedformylsulfonamide, an alpha,beta-unsaturated formylsulfonylchloride, anitro formylalkene, such as comprising a vinylogous nitro group(alpha,beta-unsaturated nitroformylalkene), wherein such reactive groupsmay optionally be protected by protection groups, for example aminoprotection groups such as for example Fmoc, for example MSc, for exampleBoc, for example 4-pentenoyl, for example o-Ns, for example p-Ns, forexample allyl carbamate, for example benzyl carbamate and a combinationthereof, for example carboxylic acid protection such as methyl ester,ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester, benzyl ester,p-methoxy benzyl ester, o-nitrobenzyl ester, methylsulfonylethyl ester,for example aldehyde protection such as an acetal or the aldehyde mayoptionally be masked as a 1,2-diol and a combination thereof, whereinsuch reactants may optionally be substituted by one or moresubstituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example an alpha,beta-unsaturated carboxyaldehyde, analpha,beta-unsaturated carboxysulfonyl chloride, analpha,beta-unsaturated carboxycarboxylic acid, an alpha,beta-unsaturatedcarboxycarboxylic acid ester, an alpha,beta-unsaturatedcarboxylsocyanate, an alpha,beta-unsaturated carboxyketone, wherein suchreactive groups may optionally be protected by protection groups, forexample amino protection groups such as for example Fmoc, for exampleMSc, for example Boc, for example 4-pentenoyl, for example o-Ns, forexample p-Ns, for example allyl carbamate, for example benzyl carbamateand a combination thereof, for example carboxylic acid protection suchas methyl ester, ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester,benzyl ester, p-methoxy benzyl ester, o-nitrobenzyl ester,methylsulfonylethyl ester, for example aldehyde protection such as anacetal or the aldehyde may optionally be masked as a 1,2-diol and acombination thereof, wherein such reactants may optionally besubstituted by one or more substituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example an alpha,beta-unsaturated alkoxycarbonylaldehyde, analpha,beta-unsaturated alkoxycarbonylsulfonyl chloride, analpha,beta-unsaturated alkoxycarbonylcarboxylic acid, an alpha,beta-unsaturated alkoxycarbonylcarboxylic acid ester, analpha,beta-unsaturated alkoxycarbonylisocyanate, analpha,beta-unsaturated alkoxycarbonylketone, wherein such reactivegroups may optionally be protected by protection groups, for exampleamino protection groups such as for example Fmoc, for example MSc, forexample Boc, for example 4-pentenoyl, for example o-Ns, for examplep-Ns, for example allyl carbamate, for example benzyl carbamate and acombination thereof, for example carboxylic acid protection such asmethyl ester, ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester,benzyl ester, p-methoxy benzyl ester, o-nitrobenzyl ester,methylsulfonylethyl ester, for example aldehyde protection such as anacetal or the aldehyde may optionally be masked as a 1,2-diol and acombination thereof, wherein such reactants may optionally besubstituted by one or more substituents.

In a further embodiment, a reactant comprises three reactive groups,such as for example an alpha,beta-unsaturated formylaldehyde, analpha,beta-unsaturated formylsulfonyl chloride, analpha,beta-unsaturated formylcarboxylic acid, an alpha,beta-unsaturatedformylcarboxylic acid ester, an alpha,beta-unsaturated formylisocyanate,an alpha,beta-unsaturated formylketone, wherein such reactive groups mayoptionally be protected by protection groups, for example aminoprotection groups such as for example Fmoc, for example MSc, for exampleBoc, for example 4-pentenoyl, for example o-Ns, for example p-Ns, forexample allyl carbamate, for example benzyl carbamate and a combinationthereof, for example carboxylic acid protection such as methyl ester,ethyl ester, t-butyl ester, 2,2,2-trichloroethyl ester, benzyl ester,p-methoxy benzyl ester, o-nitrobenzyl ester, methylsulfonylethyl ester,for example aldehyde protection such as an acetal or the aldehyde mayoptionally be masked as a 1,2-diol and a combination thereof, whereinsuch reactants may optionally be substituted by one or moresubstituents.

Further reactive group reactions are illustrated herein below. Theillustrations should not be construed as limiting the scope of thepresent invention in any way.

Nucleophilic Substitution Using Activation of Electrophiles A. AcylatingMonomer Building Blocks (Reactants)-Principle

B. Acylation

Amide Formation by Reaction of Amines with Activated Esters

C. Acylation

Pyrazolone Formation by Reaction of Hydrazines with Alpha-Ketoesters

D. Acylation

Isoxazolone Formation by Reaction of Hydroxylamines withAlpha-Ketoesters

E. Acylation

Pyrimidine Formation by Reaction of Thioureas with Alpha-Ketoesters

F. Acylation

Pyrimidine Formation by Reaction of Ureas with Malonates

G. Acylation Coumarine or Quinolinon Formation by a Heck ReactionFollowed by a Nucleophilic Substitution

H. Acylation

Phthalhydrazide formation by reaction of Hydrazines and Phthalimides

I. Acylation Diketopiperazine Formation by Reaction of Amino Acid Esters

J. Acylation Hydantoin Formation by Reaction of Urea and α-SubstitutedEsters

K. Alkylating Monomer Building Blocks (Reactants)-Principle

Alkylated Compounds by Reaction of Sulfonates with Nucleofiles

L. Vinylating Monomer Building Blocks (Reactants)-Principle

M. Heteroatom Electrophiles

Disulfide Formation by Reaction of Pyridyl Disulfide with Mercaptanes

N. Acylation Benzodiazepinone Formation by Reaction of Amino Acid Estersand Amino Ketones

Addition to Carbon-Hetero Multiple Bonds: O. Wittig/Horner-Wittig-EmmonsReagents

Substituted Alkene Formation by Reaction of Phosphonates with Aldehydesor Ketones

Transition Metal Catalysed Reactions P. Arylation

Biaryl Formation by the Reaction of Boronates with Aryls or Heteroaryls

Q. Arylation

Biaryl Formation by the Reaction of Boronates with Aryls or Heteroaryls

R. Arylation

Vinylarene Formation by the Reaction of Alkenes with Aryls orHeteroaryls

S. Alkylation

Alkylation of Arenes/Hetarens by the Reaction with Alkyl Boronates

T. Alkylation

Alkylation of Arenas/Hetarenes by Reaction with Enolethers

Nucleophilic Substitution Using Activation of Nucleophiles U.Condensations

Alkylation of Aldehydes with Enolethers or Enamines

V. Alkylation

Alkylation of Aliphatic Halides or Tosylates with Enolethers or Enamines

Cycloadditions W. [2+4] Cycloadditions

X. [2+4] Cycloadditions

Y. [3+2] Cycloadditions

Z. [3+2] Cycloadditions

The synthesis of the molecule can involve one or more of the belowillustrated reactions.

Examples of nucleophilic substitution reactions involved in one or moremolecule synthesis steps.

Aromatic nucleophilic substitutions SUBSTITUTED AROMATIC COMPOUNDS

Nu = Oxygen—, Nitrogen—, Sulfur— and Carbon Nucleophiles X = F, Cl, Br,I, OSO₂CH₃, OSO₂CF₃, OSO₂TOL ,,, etc. Z′,Z = COOR, CHO, COR, CONR″₂,COO⁻, CN, NO₂, SOR, SO₂R, SO₂NR″₂,, ect. Transition metal catalysedreactions

VINYL SUBSTITUTED AROMATIC COMPOUNDS

ALKYN SUBSTITUTED AROMATIC COMPOUNDS

BIARYL COMPOUNDS

Addition to Carbon-Carbon Multiple Bonds

Cycloaddition to Multiple Bounds

Addition to Carbon-Hetero Multiple Bonds

In the above illustrated chemical reactions, R, R′, R″, R′″, R″″, R1,R2, R3, R4, R5, R6, R7, R8, respectively, are selected independentlyfrom the group consisting of: hydrido,

substituted and unsubstituted alkyl, substituted and unsubstitutedhaloalkyl, substituted and unsubstituted hydroxyalkyl, substituted andunsubstituted alkylsulfonyl,substituted and unsubstituted alkenyl,halo,substituted and unsubstituted alkoxy, substituted and unsubstitutedalkoxyalkyl, substituted and unsubstituted haloalkoxy, substituted andunsubstituted haloalkoxyalkyl,substituted and unsubstituted aryl,substituted and unsubstituted heterocyclic,substituted and unsubstituted heteroaryl,sulfonyl, substituted and unsubstituted alkylsulfonyl, substituted andunsubstituted arylsulfonyl, sulfamyl, sulfonamidyl, aminosulfonyl,substituted and unsubstituted N-alkylaminosulfonyl, substituted andunsubstituted N-arylaminosulfonyl, substituted and unsubstitutedN,N-dialkylaminosulfonyl, substituted and unsubstitutedN-alkyl-N-arylaminosulfonyl, substituted and unsubstitutedN-alkylaminosulfonyl, substituted and unsubstitutedN,N-dialkylaminosulfonyl, substituted and unsubstitutedN-arylaminosulfonyl, substituted and unsubstitutedN-alkyl-N-arylaminosulfonyl,carboxy, substituted and unsubstituted carboxyalkyl,carbonyl, substituted and unsubstituted alkylcarbonyl, substituted andunsubstituted alkylcarbonylalkyl,substituted and unsubstituted alkoxycarbonyl, substituted andunsubstituted alkoxycarbonylalkyl,aminocarbonyl, substituted and unsubstituted aminocarbonylalkyl,substituted and unsubstituted N-alkylaminocarbonyl, substituted andunsubstituted N-arylaminocarbonyl, substituted and unsubstitutedN,N-dialkylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-arylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-hydroxyaminocarbonyl, substituted and unsubstitutedN-alkyl-N-hydroxyaminocarbonylalkyl, substituted and unsubstitutedN-alkylaminocarbonyl, substituted and unsubstitutedN,N-dialkylaminocarbonyl, substituted and unsubstitutedN-arylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-arylaminocarbonyl, substituted and unsubstitutedaminocarbonylalkyl, substituted and unsubstitutedN-cycloalkylaminocarbonyl,substituted and unsubstituted aminoalkyl, substituted and unsubstitutedalkylaminoalkyl,amidino,cyanoamidino,substituted and unsubstituted heterocyclicalkyl,substituted and unsubstituted aralkyl,substituted and unsubstituted cycloalkyl,substituted and unsubstituted cycloalkenyl,substituted and unsubstituted alkylthio,substituted and unsubstituted alkylsulfinyl,substituted and unsubstituted N-alkylamino, substituted andunsubstituted N,N-dialkylamino,substituted and unsubstituted arylamino, substituted and unsubstitutedaralkylamino, substituted and unsubstituted N-alkyl-N-arylamino,substituted and unsubstituted N-aralkyl-N-alkylamino, substituted andunsubstituted N-arylaminoalkyl, substituted and unsubstitutedN-aralkylaminoalkyl, substituted and unsubstitutedN-alkyl-N-arylaminoalkyl, substituted and unsubstitutedN-aralkyl-N-alkylaminoalkyl,acyl, acylamino,substituted and unsubstituted arylthio, substituted and unsubstitutedaralkylthio,substituted and unsubstituted aryloxy, substituted and unsubstitutedaralkoxy,substituted and unsubstituted haloaralkyl,substituted and unsubstituted carboxyhaloalkyl,substituted and unsubstituted alkoxycarbonylhaloalkyl, substituted andunsubstituted aminocarbonylhaloalkyl, substituted and unsubstitutedalkylaminocarbonylhaloalkyl,substituted and unsubstituted alkoxycarbonylcyanoalkenyl,substituted and unsubstituted carboxyalkylaminocarbonyl,substituted and unsubstituted aralkoxycarbonylalkylaminocarbonyl,substituted and unsubstituted cycloalkylalkyl, andsubstituted and unsubstituted aralkenyl.

Further reaction schemes in accordance with the present invention aredisclosed herein below.

A. Acylation Reactions

General route to the formation of acylating reactants and the use ofthese:

N-hydroxymaleimide (1) may be acylated by the use of an acylchloridee.g. acetylchloride or alternatively acylated in e.g. THF by the use ofdicyclohexylcarbodiimide or diisopropylcarbodiimide and acid e.g. aceticacid. The intermediate may be subjected to Michael addition by the useof excess 1,3-propanedithiol, followed by reaction with either4,4′-dipyridyl disulfide or 2,2′-dipyridyl disulfide. This intermediate(3) may then be loaded onto an oligonucleotide carrying a thiol handleto generate the reactant (4). Obviously, the intermediate (2) can beattached to the oligonucleotide using another linkage than the disulfidelinkage, such as an amide linkage and the N-hydroxymaleimide can bedistanced from the oligonucleotide using a variety of spacers.

The reactant (4) may be reacted with an identifier oligonucleotidecomprising a recipient amine group e.g. by following the procedure: Thereactant (4) (1 nmol) is mixed with an amino-oligonucleotide (1 nmol) inhepes-buffer (20 μL of a 100 mM hepes and 1 M NaCl solution, pH=7.5) andwater (39 uL). The oligonucleotides are annealed together by heating to50° C. and cooling (2° C./second) to 30° C. The mixture is then left o/nat a fluctuating temperature (10° C. for 1 second then 35° C. for 1second), to yield the product (5).

In more general terms, the reactants indicated below is capable oftransferring a chemical entity (CE) to a recipient nucleophilic group,typically an amine group. The bold lower horizontal line illustrates thereactant and the vertical line illustrates a spacer. The 5-memberedsubstituted N-hydroxysuccinimid (NHS) ring serves as an activator, i.e.a labile bond is formed between the oxygen atom connected to the NHSring and the chemical entity. The labile bond may be cleaved by anucleophilic group, e.g. positioned on a scaffold

Another reactant which may form an amide bond is

R may be absent or NO₂, CF₃, halogen, preferably Cl, Br, or I, and Z maybe S or O. This type of reactant is disclosed in Danish patentapplication No. PA 2002 0951 and US provisional patent application filed20 Dec. 2002 with the title “A reactant capable of transferring afunctional entity to a recipient reactive group”. The content of bothpatent application are incorporated herein in their entirety byreference.

A nucleophilic group can cleave the linkage between Z and the carbonylgroup thereby transferring the chemical entity —(C═O)—CE′ to saidnucleophilic group.

CE and CE′ are preferably selected from the group consisting of:

hydrido,substituted and unsubstituted alkyl, substituted and unsubstitutedhaloalkyl, substituted and unsubstituted hydroxyalkyl, substituted andunsubstituted alkylsulfonyl,substituted and unsubstituted alkenyl,halo,substituted and unsubstituted alkoxy, substituted and unsubstitutedalkoxyalkyl, substituted and unsubstituted haloalkoxy, substituted andunsubstituted haloalkoxyalkyl,substituted and unsubstituted aryl,substituted and unsubstituted heterocyclic,substituted and unsubstituted heteroaryl,sulfonyl, substituted and unsubstituted alkylsulfonyl, substituted andunsubstituted arylsulfonyl, sulfamyl, sulfonamidyl, aminosulfonyl,substituted and unsubstituted N-alkylaminosulfonyl, substituted andunsubstituted N-arylaminosulfonyl, substituted and unsubstitutedN,N-dialkylaminosulfonyl, substituted and unsubstitutedN-alkyl-N-arylaminosulfonyl, substituted and unsubstitutedN-alkylaminosulfonyl, substituted and unsubstitutedN,N-dialkylaminosulfonyl, substituted and unsubstitutedN-arylaminosulfonyl, substituted and unsubstitutedN-alkyl-N-arylaminosulfonyl,carboxy, substituted and unsubstituted carboxyalkyl, carbonyl,substituted and unsubstituted alkylcarbonyl, substituted andunsubstituted alkylcarbonylalkyl,substituted and unsubstituted alkoxycarbonyl, substituted andunsubstituted alkoxycarbonylalkyl,aminocarbonyl, substituted and unsubstituted aminocarbonylalkyl,substituted and unsubstituted N-alkylaminocarbonyl, substituted andunsubstituted N-arylaminocarbonyl, substituted and unsubstitutedN,N-dialkylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-arylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-hydroxyaminocarbonyl, substituted and unsubstitutedN-alkyl-N-hydroxyaminocarbonylalkyl, substituted and unsubstitutedN-alkylaminocarbonyl, substituted and unsubstitutedN,N-dialkylaminocarbonyl, substituted and unsubstitutedN-arylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-arylaminocarbonyl, substituted and unsubstitutedaminocarbonylalkyl, substituted and unsubstitutedN-cycloalkylaminocarbonyl,substituted and unsubstituted aminoalkyl, substituted and unsubstitutedalkylaminoalkyl,amidino,cyanoamidino,substituted and unsubstituted heterocyclicalkyl,substituted and unsubstituted aralkyl,substituted and unsubstituted cycloalkyl,substituted and unsubstituted cycloalkenyl,substituted and unsubstituted alkylthio,substituted and unsubstituted alkylsulfinyl,substituted and unsubstituted N-alkylamino, substituted andunsubstituted N,N-dialkylamino,substituted and unsubstituted arylamino, substituted and unsubstitutedaralkylamino, substituted and unsubstituted N-alkyl-N-arylamino,substituted and unsubstituted N-aralkyl-N-alkylamino, substituted andunsubstituted N-arylaminoalkyl, substituted and unsubstitutedN-aralkylaminoalkyl, substituted and unsubstitutedN-alkyl-N-arylaminoalkyl, substituted and unsubstitutedN-aralkyl-N-alkylaminoalkyl,acyl, acylamino,substituted and unsubstituted arylthio, substituted and unsubstitutedaralkylthio,substituted and unsubstituted aryloxy, substituted and unsubstitutedaralkoxy,substituted and unsubstituted haloaralkyl,substituted and unsubstituted carboxyhaloalkyl,substituted and unsubstituted alkoxycarbonylhaloalkyl, substituted andunsubstituted aminocarbonylhaloalkyl, substituted and unsubstitutedalkylaminocarbonylhaloalkyl,substituted and unsubstituted alkoxycarbonylcyanoalkenyl,substituted and unsubstituted carboxyalkylaminocarbonyl,substituted and unsubstituted aralkoxycarbonylalkylaminocarbonyl,substituted and unsubstituted cycloalkylalkyl, andsubstituted and unsubstituted aralkenyl.

B. Alkylation

General route to the formation of alkylating/vinylating reactants anduse of these:

Alkylating Reactants may have the Following General Structure:

R¹ and R² may be used to tune the reactivity of the sulphate to allowappropriate reactivity. Chloro and nitro substitution will increasereactivity. Alkyl groups will decrease reactivity. Ortho substituents tothe sulphate will due to steric reasons direct incoming nucleophiles toattack the R-group selectively and avoid attack on sulphur.

An example of the formation of an alkylating reactant and the transferof a functional entity is depicted below:

3-Aminophenol (6) is treated with maleic anhydride, followed bytreatment with an acid e.g. H₂SO₄ or P₂O₅ and heated to yield themaleimide (7). The ring closure to the maleimide may also be achievedwhen an acid stable O-protection group is used by treatment with Ac₂O,with or without heating, followed by O-deprotection. Alternativelyreflux in Ac₂O, followed by O-deacetylation in hot water/dioxane toyield (7).

Further treatment of (7) with SO₂Cl₂, with or without triethylamine orpotassium carbonate in dichloromethane or a higher boiling solvent willyield the intermediate (8), which may be isolated or directly furthertransformed into the aryl alkyl sulphate by the quench with theappropriate alcohol, in this case MeOH, whereby (9) will be formed.

The organic moiety (9) may be connected to an oligonucleotide, asfollows: A thiol carrying oligonucleotide in buffer 50 mM MOPS or hepesor phosphate pH 7.5 is treated with a 1-100 mM solution and preferably7.5 mM solution of the organic reactant (9) in DMSO or alternativelyDMF, such that the DMSO/DMF concentration is 5-50%, and preferably 10%.The mixture is left for 1-16 h and preferably 2-4 h at 25° C. to givethe alkylating agent in this case a methylating reactant (10).

The reaction of the alkylating reactant (10) with an amine bearingnascent bifunctional complex may be conducted as follows: Thebifunctional complex (1 nmol) is mixed the reactant (10) (1 nmol) inhepes-buffer (20 μL of a 100 mM hepes and 1 M NaCl solution, pH=7.5) andwater (39 uL). The oligonucleotides are annealed to each other byheating to 50° C. and cooled (2° C./second) to 30° C. The mixture isthen left o/n at a fluctuating temperature (10° C. for 1 second then 35°C. for 1 second), to yield the methylamine reaction product (11).

In more general terms, a reactant capable of transferring a chemicalentity to a receiving reactive group forming a single bond is

The receiving group may be a nucleophile, such as a group comprising ahetero atom, thereby forming a single bond between the chemical entityand the hetero atom, or the receiving group may be an electronegativecarbon atom, thereby forming a C—C bond between the chemical entity andthe scaffold.

CE is defined as herein above under section A (acylation reactions).

C. Vinylation Reactions

A vinylating reactant may be prepared and used similarly as describedabove for an alkylating reactant. Although instead of reacting thechlorosulphonate (8 above) with an alcohol, the intermediatechlorosulphate is isolated and treated with an enolate orO-trialkylsilylenolate with or without the presence of fluoride. E.g.

Formation of an Exemplary Vinylating Reactant (13):

The thiol carrying oligonucleotide in buffer 50 mM MOPS or hepes orphosphate pH 7.5 is treated with a 1-100 mM solution and preferably 7.5mM solution of the organic moiety (12) in DMSO or alternatively DMF,such that the DMSO/DMF concentration is 5-50%, and preferably 10%. Themixture is left for 1-16 h and preferably 2-4 h at 25° C. to give thevinylating reactant (13).

The sulfonylenolate (13) may be used to react with amine carryingscaffold to give an enamine (14a and/or 14b) or e.g. react with acarbanion to yield (15a and/or 15b). E.g.

The reaction of the vinylating reactant (13) and an amine or nitroalkylcarrying identifier may be conducted as follows:

The amino-oligonucleotide (1 nmol) or nitroalkyl-oligonucleotide (1nmol) identifier is mixed with the reactant (1 nmol) (13) in 0.1 M TAPS,phosphate or hepes-buffer and 300 mM NaCl solution, pH=7.5-8.5 andpreferably pH=8.5. The oligonucleotides are annealed to the template byheating to 50° C. and cooled (2° C./second) to 30° C. The mixture isthen left o/n at a fluctuating temperature (10° C. for 1 second then 35°C. for 1 second), to yield reaction product (14a/b or 15a/b).Alternative to the alkyl and vinyl sulphates described above may equallyeffective be sulphonates as e.g. (31) (however with R″ instead as alkylor vinyl), described below, prepared from (28, with the phenyl groupsubstituted by an alkyl group) and (29), and be used as alkylating andvinylating agents.

Another reactant capable of forming a double bond by the transfer of achemical entity to a recipient aldehyde group is shown below. A doublebond between the carbon of the aldehyde and the chemical entity isformed by the reaction.

The above reactant is comprised by the Danish patent application No. DKPA 2002 01952 and the US provisional patent application filed 20 Dec.2002 with the title “A reactant capable of transferring a functionalentity to a recipient reactive group forming a C═C double bond”. Thecontent of both patent applications are incorporated herein in theirentirety by reference.

CE is defined as herein above under section A (acylation reactions).

D. Alkenylidation Reactions

General route to the formation of Wittig and HWE reactants and use ofthese:

Commercially available compound (16) may be transformed into the NHSester (17) by standard means, i.e. DCC or DIC couplings. An aminecarrying oligonucleotide in buffer 50 mM MOPS or hepes or phosphate pH7.5 is treated with a 1-100 mM solution and preferably 7.5 mM solutionof the organic compound in DMSO or alternatively DMF, such that theDMSO/DMF concentration is 5-50%, and preferably 10%. The mixture is leftfor 1-16 h and preferably 2-4 h at 25° C. to give the phosphine boundprecursor reactant (18). This precursor reactant is further transformedby addition of the appropriate alkylhalide, e.g.N,N-dimethyl-2-iodoacetamide as a 1-100 mM and preferably 7.5 mMsolution in DMSO or DMF such that the DMSO/DMF concentration is 5-50%,and preferably 10%. The mixture is left for 1-16 h and preferably 2-4 hat 25° C. to give the reactant (19). As an alternative to this, theorganic compound (17) may be P-alkylated with an alkylhalide and then becoupled onto an amine carrying oligonucleotide to yield (19).

An aldehyde carrying identifier (20), may be formed by the reactionbetween the NHS ester of 4-formylbenzoic acid and an amine carryingoligonucleotide, using conditions similar to those described above. Theidentifier (20) reacts with (19) under slightly alkaline conditions toyield the alkene (21).

The reaction of monomer reactants (19) and identifier (20) may beconducted as follows: The identifier (20) (1 nmol) is mixed withreactant (19) (1 nmol) in 0.1 M TAPS, phosphate or hepes-buffer and 1 MNaCl solution, pH=7.5-8.5 and preferably pH=8.0. The reaction mixture isleft at 35-65° C. preferably 58° C. over night to yield reaction product(21).

As an alternative to (17), phosphonates (24) may be used instead. Theymay be prepared by the reaction between diethylchlorophosphite (22) andthe appropriate carboxy carrying alcohol. The carboxylic acid is thentransformed into the NHS ester (24) and the process and alternativesdescribed above may be applied. Although instead of a simpleP-alkylation, the phosphite may undergo Arbuzov's reaction and generatethe phosphonate. Reactant (25) benefits from the fact that it is morereactive than its phosphonium counterpart (19).

E. Transition Metal Catalyzed Arylation, Hetarylation and VinylationReactions

Electrophilic reactants (31) capable of transferring an aryl, hetaryl orvinyl functionality may be prepared from organic compounds (28) and (29)by the use of coupling procedures for maleimide derivatives toSH-carrying oligonucleotides described above. Alternatively to themaleimide the NHS-ester derivatives may be prepared from e.g.carboxybenzensulfonic acid derivatives, be used by coupling of these toan amine carrying oligonucleotide. The R-group of (28) and (29) is usedto tune the reactivity of the sulphonate to yield the appropriatereactivity.

The transition metal catalyzed cross coupling may be conducted asfollows: A premix of 1.4 mM Na₂PdCl₄ and 2.8 mM P(p-SO₃C₆H₄)₃ in waterleft for 15 min was added to a mixture of the identifier (30) andreactant (31) (both 1 nmol) in 0.5 M NaOAc buffer at pH=5 and 75 mM NaCl(final [Pd]=0.3 mM). The mixture is then left o/n at 35-65° C.preferably 58° C., to yield reaction product (32).

Corresponding nucleophilic monomer reactants capable of transferring anaryl, hetaryl or vinyl functionality may be prepared from organiccompounds of the type (35). This is available by estrification of aboronic acid by a diol e.g. (33), followed by transformation into theNHS-ester derivative. The NHS-ester derivative may then be coupled to anoligonucleotide, by use of coupling procedures for NHS-ester derivativesto amine carrying oligonucleotides described above, to generate reactanttype (37). Alternatively, maleimide derivatives may be prepared asdescribed above and loaded onto SH-carrying oligonucleotides.

The transition metal catalyzed cross coupling is conducted as follows: Apremix of 1.4 mM Na₂PdCl₄ and 2.8 mM P(p-SO₃C₆H₄)₃ in water left for 15min was added to a mixture of the identifier (36) and the reactant (37)(both 1 nmol) in 0.5 M NaOAc buffer at pH=5 and 75 mM NaCl (final[Pd]=0.3 mM). The mixture is then left o/n at 35-65° C. preferably 58°C., to yield template bound (38).

F. Reactions of Enamine and Enolether Monomer Reactants

Reactants loaded with enamines and enolethers may be prepared asfollows: For Z=NHR (R=H, alkyl, aryl, hetaryl), a 2-mercaptoethylaminemay be reacted with a dipyridyl disulfide to generate the activateddisulfide (40), which may then be condensed to a ketone or an aldehydeunder dehydrating conditions to yield the enamine (41). For Z=OH,2-mercaptoethanol is reacted with a dipyridyl disulfide, followed byO-tosylation (Z=OTs). The tosylate (40) may then be reacted directlywith an enolate or in the presence of fluoride with aO-trialkylsilylenolate to generate the enolate (41).

The enamine or enolate (41) may then be coupled onto an SH-carryingoligonucleotide as described above to give the reactant (42).

The reactant (42) may be reacted with a carbonyl carrying identifieroligonucleotide like (44) or alternatively an alkylhalide carryingoligonucleotide like (43) as follows: The reactant (42) (1 nmol) ismixed with the identifier (43) (1 nmol) in 50 mM MOPS, phosphate orhepes-buffer buffer and 250 mM NaCl solution, pH=7.5-8.5 and preferablypH=7.5. The reaction mixture is left at 35-65° C. preferably 58° C. overnight or alternatively at a fluctuating temperature (10° C. for 1 secondthen 35° C. for 1 second) to yield reaction product (46), where Z=O orNR. For compounds where Z=NR slightly acidic conditions may be appliedto yield product (46) with Z=O.

The reactant (42) (1 nmol) is mixed with the identifier (44) (1 nmol) in0.1 M TAPS, phosphate or hepes-buffer buffer and 300 mM NaCl solution,pH=7.5-8.5 and preferably pH=8.0. The reaction mixture is left at 35-65°C. preferably 58° C. over night or alternatively at a fluctuatingtemperature (10° C. for 1 second then 35° C. for 1 second) to yieldreaction product (45), where Z=O or NR. For compounds where Z=NRslightly acidic conditions may be applied to yield product (45) withZ=O.

Enolethers type (13) may undergo cycloaddition with or withoutcatalysis. Similarly, dienolethers may be prepared and used, e.g. byreaction of (8) with the enolate or trialkylsilylenolate (in thepresence of fluoride) of an α,β-unsaturated ketone or aldehyde togenerate (47), which may be loaded onto an SH-carrying oligonucleotide,to yield monomer reactant (48).

The diene (49), the ene (50) and the 1,3-dipole (51) may be formed bysimple reaction between an amino carrying oligonucleotide and theNHS-ester of the corresponding organic compound. Reaction of (13) oralternatively (31, R″=vinyl) with dienes as e.g. (49) to yield (52) ore.g. 1,3-dipoles (51) to yield (53) and reaction of (48) or (31,R″=dienyl) with enes as e.g. (50) to yield (54) may be conducted asfollows:

The reactant (13) or (48) (1 nmol) is mixed with the identifier (49) or(50) or (51) (1 nmol) in 50 mM MOPS, phosphate or hepes-buffer bufferand 2.8 M NaCl solution, pH=7.5-8.5 and preferably pH=7.5. The reactionmixture is left at 35-65° C. preferably 58° C. over night oralternatively at a fluctuating temperature (10° C. for 1 second then 35°C. for 1 second) to yield template bound (52), (53) or (54),respectively.

Cross-Link Cleavage Reactants

It may be advantageous to split the transfer of a chemical entity to arecipient reactive group into two separate steps, namely a cross-linkingstep and a cleavage step because each step can be optimized. A suitablereactant for this two step process is illustrated below:

Initially, a reactive group appearing on the functional entity precursor(abbreviated FEP) reacts with a recipient reactive group, e.g. areactive group appearing on a scaffold, thereby forming a cross-link.Subsequently, a cleavage is performed, usually by adding an aqueousoxidising agent such as I₂, Br₂, Cl₂, H⁺, or a Lewis acid. The cleavageresults in a transfer of the group HZ-FEP- to the recipient moiety, suchas a scaffold.

In the above formula

Z is O, S, NR⁴

Q is N, CR¹

P is a valence bond, O, S, NR⁴, or a group C₅₋₇arylene, C₁₋₆alkylene,C₁₋₆O-alkylene, C₁₋₆S-alkylene, NR¹-alkylene, C₁₋₆alkylene-O,C₁₋₆alkylene-S option said group being substituted with 0-3 R⁴, 0-3 R⁵and 0-3 R⁹ or C₁-C₃ alkylene-NR⁴ ₂, C₁-C₃ alkylene-NR⁴C(O)R⁸, C₁-C₃alkylene-NR⁴C(O)OR⁸, C₁-C₂ alkylene-O—NR⁴ ₂, C₁-C₂ alkylene-O—NR⁴C(O)R⁸,C₁-C₂ alkylene-O—NR⁴C(O)OR⁸ substituted with 0-3 R⁹,

B is a group comprising D-E-F, in which

D is a valence bond or a group C₁₋₆alkylene, C₁₋₆alkenylene,C₁₋₆alkynylene, C₅₋₇arylene, or C₅₋₇heteroarylene, said group optionallybeing substituted with 1 to 4 group R¹¹,

E is, when present, a valence bond, O, S, NR⁴, or a group C₁₋₆alkylene,C₁₋₆alkenylene, C₁₋₆alkynylene, C₅₋₇arylene, or C₅₋₇heteroarylene, saidgroup optionally being substituted with 1 to 4 group R¹¹,

F is, when present, a valence bond, O, S, or NR⁴,

A is a spacing group distancing the chemical structure from thecomplementing element, which may be a nucleic acid,

R¹, R², and R³ are independent of each other selected among the groupconsisting of H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₄-C₈alkadienyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, andheteroaryl, said group being substituted with 0-3 R⁴, 0-3 R⁵ and 0-3 R⁹or C₁-C₃ alkylene-NR⁴ ₂, C₁-C₃ alkylene-NR⁴C(O)R⁸, C₁-C₃alkylene-NR⁴C(O)OR⁸, C₁-C₂ alkylene-O—NR⁴ ₂, C₁-C₂ alkylene-O—NR⁴C(O)R⁸,C₁-C₂ alkylene-O—NR⁴C(O)OR⁸ substituted with 0-3 R⁹,

FEP is a group selected among the group consisting of H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₄-C₈ alkadienyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl, and heteroaryl, said group being substitutedwith 0-3 R⁴, 0-3 R⁵ and 0-3 R⁹ or C₁-C₃ alkylene-NR⁴ ₂, C₁-C₃alkylene-NR⁴C(O)R⁸, C₁-C₃ alkylene-NR⁴C(O)OR⁸, C₁-C₂ alkylene-O—NR⁴ ₂,C₁-C₂ alkylene-O—NR⁴C(O)R⁸, C₁-C₂ alkylene-O—NR⁴C(O)OR⁸ substituted with0-3 R⁹,

where R⁴ is H or selected independently among the group consisting ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, aryl, heteroaryl, said group being substituted with0-3 R⁹ and

R⁵ is selected independently from —N₃, —CNO, —C(NOH)NH₂, —NHOH, —NHNHR⁶,—C(O)R⁶, —SnR⁶ ₃, —B(OR⁶)₂, —P(O) (OR⁶)₂ or the group consisting ofC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₄-C₈ alkadienyl said group beingsubstituted with 0-2 R⁷,

where R⁶ is selected independently from H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, aryl or C₁-C₆ alkylene-aryl substituted with 0-5 halogenatoms selected from —F, —Cl, —Br, and —I; and R⁷ is independentlyselected from —NO₂, —COOR⁶, —COR⁶, —CN, —OSiR⁶ ₃, —OR⁶ and —NR⁶ ₂.

R⁸ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,aryl or C₁-C₆ alkylene-aryl substituted with 0-3 substituentsindependently selected from —F, —Cl, —NO₂, —R³, —OR³—SiR³ ₃

R⁹ is ═O, —F, —Cl, —Br, —I, —CN, —NO₂, —OR⁶, —NR⁶ ₂, —NR⁶—C(O)R⁸,—NR⁶—C(O)OR⁸, —SR⁶, —S(O)R⁶, —S(O)₂R⁶, —COOR⁶, —C(O)NR⁶ ₂ and —S(O)₂NR⁶₂.

In a preferred embodiment Z is O or S, P is a valence bond, Q is CH, Bis CH₂, and R¹, R², and R³ is H. The bond between the carbonyl group andZ is cleavable with aqueous I₂.

Reactant Reactions and Molecules Generated by such Reactions

A reactant can participate in a reaction with the chemical reaction siteand/or in a reaction with other reactants and contributes to the achemical structure of the final molecule. The reaction between thechemical reaction site and the one or more reactants, or betweenindividual reactants, can take place under suitable conditions thatfavours the reaction.

Generally, a molecule is formed by reacting several chemical entitieswith each other and/or with a chemical reaction site, such as a scaffoldmoiety comprising a plurality of reactive groups or sites. In oneembodiment of the invention, a nascent bifunctional complex is reactedwith one or more reactants and with the respective tag(s) more than oncepreferably using a split-and-mix technique. The reactions can berepeated as often as necessary in order to obtain a molecule as one partof the bifunctional complex and an identifying oligonucleotidecomprising the tags identifying the reactants which participated in theformation of the molecule.

The synthesis of a molecule according to the methods of the presentinvention can proceed via particular type(s) of coupling reaction(s),such as, but not limited to, one or more of the reactive group reactionscited herein above. In some embodiments, combinations of two or morereactive group reactions will occur, such as combinations of two or moreof the reactive group reactions discussed above, or combinations of thereactions disclosed in Table 1. For example, reactants can be joined bya combination of amide bond formation (amino and carboxylic acidcomplementary groups) and reductive amination (amino and aldehyde orketone complementary groups).

The reaction of the reactant(s) with each other and/or with the chemicalreaction site on the one hand and the reaction of tag(s) with each otherand/or with the priming site on the other hand may occur sequentially inany order or simultaneously. The choice of order can be influenced bye.g. type of enzyme, reaction conditions used, and the type ofreactant(s). The chemical reaction site can comprise a single ormultiple reactive groups capable of reacting with one or more reactants.In a certain aspect the chemical reaction site comprises a scaffoldhaving one or more reactive groups attached.

A round or cycle of reaction can imply that a) a single reactant isreacted with the chemical reaction site, such as a scaffold, or with oneor more reactant(s) having reacted with the chemical reaction siteduring a previous reaction round, and b) that the respectiveoligonucleotide tag identifying the reactant is reacted with another tagor with the priming site. However, a round or cycle of reaction can alsoimply that a) multiple reactants are reacted with the chemical reactionsite, such as a scaffold, or with one or more reactant(s) having reactedwith the chemical reaction site during a previous reaction round, and b)that respective oligonucleotide tags identifying the reactants arereacted with each other and/or with another tag and/or with the primingsite. At least one tag reaction resulting in the tag being attached toanother tag or to the priming site involves one or more enzymes.

A reactant comprising one or more chemical entities and one or morereactive groups can have any chemical structure. At least one reactivegroup, or a precursor thereof, reacts with the chemical reaction site orone or more reactive group(s) of one or more other reactants. A“bridging molecule” can act to mediate a connection or form a bridgebetween two reactants or between a reactant and a chemical reactionsite.

The invention can be performed by reacting a single reactant with thenascent bifunctional complex and add the corresponding tag. However, itmay be preferred to build a molecule comprising the reaction product oftwo of more reactants. Thus, in a certain aspect of the invention amethod is devised for obtaining a bifunctional complex composed of amolecule part and a single stranded identifier oligonucleotide, saidmolecule part being the reaction product of reactants and the chemicalreaction site of the initial complex.

In one embodiment of the invention, parallel syntheses are performed sothat a tag is enzymatical linked to a nascent bifunctional complex inparallel with a reaction between a chemical reaction site and areactant. In each round the addition of the tag is followed or precededby a reaction between reactant and the chemical reaction site. In eachsubsequent round of parallel syntheses the reaction product of theprevious reactions serves as the chemical reaction site and thelast-incorporated tag provides for a priming site which allows for theenzymatical addition a tag. In other aspects of the invention, two ormore tags are provided prior to or subsequent to reaction with therespective reactants.

The single stranded identifier oligonucleotide comprising covalentlyligated tags can be transformed to a double stranded form by anextension process in which a primer is annealed to the 3′ end of thesingle stranded identifier oligonucleotide and extended using a suitablepolymerase. The double strandness can be an advantage during subsequentselection processes.

Reactants comprising chemical entities and reactive groups can besynthesised e.g. as disclosed by Dolle et al. (Dolle, R. E. Mol. Div.; 3(1998) 199-233; Dolle, R. E. Mol. Div.; 4 (1998) 233-256; Dolle, R. E.;Nelson, K. H., Jr. J. Comb. Chem.; 1 (1999) 235-282; Dolle, R. E. J.Comb. Chem.; 2 (2000) 383-433; Dolle, R. E. J. Comb. Chem.; 3 (2001)477-517; Dolle, R. E. J. Comb. Chem.; 4 (2002) 369-418; Dolle, R. E. J.Comb. Chem.; 5 (2003) 693-753; Dolle, R. E. J. Comb. Chem.; 6 (2004)623-679; Dolle, R. E. J. Comb. Chem.; 7 (2005) 739-798; Dolle, R. E.; LeBourdonnec, B.; Morales, G. A.; Moriarty, K. J.; Salvino, J. M., J.Comb. Chem.; 8 (2006) 597-635 and references cited therein.(incorporated by reference herein in their entirety).

Reactants may furthermore be formed by use of solid phase synthesis orby in solution synthesis. Reactants may also be commercially available.Reactants may be produced by conventional organic synthesis, parallelsynthesis or combinatorial chemistry methods.

Protection Groups

Reactive groups may optionally be protected using protection groupchemistries as e.g. described by Green T. W. and Wuts P. G. M inProtection Groups in Organic Synthesis, Wiley, 1999, ISBN: 0-471-16019-9which is hereby incorporated by reference.

In one embodiment amines may optionally be protected as carbamates, suchas for example methyl carbamate, ethyl carbamate, t-butyl carbamate(Boc), 9-fluorenylmethyl carbamate (Fmoc), 2,2,2-trichlorethylcarbamate, 2-trimethylsilylethyl carbamate, vinyl carbamate, allylcarbamate, benzyl carbamate, p-methoxybenzyl carbamate, p-nitrobenzylcarbamate, m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,alpha-methylnitropiperonyl carbamate, o-nitrophenyl carbamate,3,4-dimethoxy-6-nitro carbamate, phenyl(o-nitrophenyl)methyl carbamate,2-(2-nitrophenyl)ethyl carbamate, 6-nitroveratryl carbamate,4-methoxyphenacyl carbamate, methylsulfonylethyl carbamate (MSc), whichmay optionally be deprotected as appropriate according to literatureprocedures as described by Green T. W. and Wuts P. G. M in ProtectionGroups in Organic Synthesis, Wiley, 1999.

In another embodiment amines may optionally be protected as amides, suchas for example trifluoroacetamide, trichloroacetamide, 4-pentenoic acidamide, o-(benzoyloxymethyl)benzamide, 2-(acetoxymethyl)benzamide,N-phthalimide, N-tetrachlorophthalimide, a nosyl (Ns) protection group,such as for example an o-nitrophenylsulfonamide (o-Ns), for example anp-nitrophenylsulfonylsulfonamide (p-Ns), which may optionally bedeprotected as appropriate according to literature procedures asdescribed by Green T. W. and Wuts P. G. M in Protection Groups inOrganic Synthesis, Wiley, 1999.

In a further embodiment amines may optionally be protected astriphenylmethyl amine (trityl, Trt), di(p-methoxyphenyl)phenylmethyl(DMT) amine, which may optionally be deprotected as appropriateaccording to literature procedures as described by Green T. W. and WutsP. G. M in Protection Groups in Organic Synthesis, Wiley, 1999.

In one embodiment carboxylic acids may optionally be protected such asfor example methyl ester, ethyl ester, t-butyl ester, benzyl ester,p-methoxy benzyl ester, 9-fluorenylmethyl ester, methoxy methyl ester,benzyloxy methyl ester, cyanomethyl ester, phenacyl ester, p-methoxyphenacyl ester, 2,2,2-trichloroethyl ester, vinyl ester, allyl ester,triethylsilyl ester, t-butyldimethylsilyl ester, phenyldimethylsilylester, triphenylmethyl ester, di(p-methoxyphenyl)phenylmethyl ester,methyl sulfonylethyl ester, which may optionally be deprotected asappropriate according to literature procedures as described by Green T.W. and Wuts P. G. M in Protection Groups in Organic Synthesis, Wiley,1999.

In one embodiment hydroxyl groups may optionally be protected such asfor example methyl ether, methoxymethyl ether, benzyloxymethyl ether,p-methoxybenzyloxymethyl ether, o-nitrobenzyloxymethyl ether,tetrahydropyranyl ether, tetrahydrofuranyl ether, ethoxyethyl ether,2,2,2-trichloroethyl ether, allyl ether, vinyl ether, benzyl ether,p-methoxybenzyl ether, o-nitrobenzyl ether, triphenylmethyl ether,di(p-methoxyphenyl)phenylmethyl ether, which may optionally bedeprotected as appropriate according to literature procedures asdescribed by Green T. W. and Wuts P. G. M in Protection Groups inOrganic Synthesis, Wiley, 1999.

In another embodiment hydroxyl groups may optionally be protected suchas for example formic acid ester, acetic acid ester, trichloroaceticacid ester, trifluoroacetic acid ester, which may optionally bedeprotected as appropriate according to literature procedures asdescribed by Green T. W. and Wuts P. G. M in Protection Groups inOrganic Synthesis, Wiley, 1999.

In a further embodiment hydroxyl groups may optionally be protected suchas for example methyl carbonates, methoxymethyl carbonates,9-fluorenylmethyl carbonates, ethyl carbonates, 2,2,2-trichloroethylcarbonates, allyl carbonates, vinyl carbonates, t-butyl carbonates,benzyl carbonates, p-methoxybenzyl carbonates, tosylate, which mayoptionally be deprotected as appropriate according to literatureprocedures as described by Green T. W. and Wuts P. G. M in ProtectionGroups in Organic Synthesis, Wiley, 1999.

In one embodiment carbonyl groups may optionally be protected such asfor example dimethyl acetal and ketal, dibenzyl acetal and ketal,1,3-dioxanes, 1,3-dioxolanes, 1,3-dithiane, 1,3-dithiolane,S,S′-dimethyl thioacetal and ketal, which may optionally be deprotectedas appropriate according to literature procedures as described by GreenT. W. and Wuts P. G. M in Protection Groups in Organic Synthesis, Wiley,1999.

In another embodiment aldehydes may optionally be masked as 1,2-diols,which may optionally be demasked by use of periodate. For example:

1. Dry down 1-20 nmol diol functionalised oligo

2. Add 25 μl NaIO₄ (50 mM in Sodium Acetate Buffer pH 4)

3. Shake at 25° C. for 30 min.

4. Add 25 μl 700 mM Phosphate buffer pH 6.7

5. Purify by P6 spin column

6. Dry down the aldehyde functionalized oligo (temperature max. 45° C.)

The following procedures may be applied for deprotection of protectiongroups. Other methods may also be applied as described in the literatureand by Green T. W. and Wuts P. G. M in Protection Groups in OrganicSynthesis, Wiley, 1999:

Procedure for tBu Ester and N-Boc Deprotection

-   -   1. Dry down functionalised oligo in an PCR tube    -   2. Add 20 μL 37.5 mM NaOAc and 5 μL 1 M MgCl₂    -   3. Incubate at 70° C. ON (Lid 100° C.) in PCR-machine    -   4. Add 45 μL H₂O    -   5. Purify by P6 spin column

Procedure Fmoc Deprotection in Water

-   -   1. Dry down oligo    -   2. Add 6% piperidine/H₂O 10 μL    -   3. Shake 30 min at 25° C.    -   4. Add 40 μL H₂O    -   5. Purify by P6 spin column

Procedure Msc Deprotection in Water

-   -   1. Dry down oligo    -   2. Dissolve in 25 μL Sodium Borate Buffer (0.1 M, pH=10)    -   3. Shake 3 h at 40° C.    -   4. Add 25 μL Water    -   5. Purify by P6 spin column        Deprotection of tBu, Me and Et Esters    -   1. Dry down oligo in an PCR tube    -   2. Add 20 μL 100 mM LiOH, seal tube    -   3. Incubate at 80° C. in PCR machine for 30 minutes    -   4. Add 40 μL 100 mM NaOAc buffer pH 5    -   5. Purify by P6 spin column

Procedure for Fmoc Deprotection on DEAE Sepharose

-   -   1) 100 μL DEAE suspension is pipetted into a filtertube and        drained by vacuum.    -   2) Add water (200 μL) and drain.    -   3) Bind solution (H₂O (200 μL)) is added. Shake 10 min 600 rpm,        then drain.    -   4) Bind solution (H₂O (100 uL) is added. No drain!    -   5) Oligo dissolved in H₂O (max. 50 μL) is added. Shake 10 min        600 rpm, then drain.    -   6) H₂O is added (200 μL). Drain.    -   7) DMF is added (200 μL). Drain.    -   8) Repeat step 11 twice.    -   9) 10% piperidine/DMF (250 μL) is added. Shake 5 min 600 rpm.        Spin 1000 g 1 min.    -   10) Repeat step 13.    -   11) DMF is added (200 μL). Drain.    -   12) Repeat step 15 twice    -   13) H₂O is added (200 μL). Drain.    -   14) Repeat step 17    -   15) Release solution is added (35 μL, 2M TEAB). Shake 10 min 600        rpm. Spin at 1000 g for 1 min, collect the solvent in an        eppendorf tube.    -   16) Repeat step 19.    -   17) Combine the solvents from step 19 and 20, then spin column        filtrate the sample.

Procedure for Ns Deprotection on DEAE Sepharose

-   -   1) 100 μL DEAE suspension is pipetted into a filtertube and        drained by vacuum.    -   2) Add water (200 μL) and drain.    -   3) Bind solution (H₂O (200 μL)) is added. Shake 10 min 600 rpm,        then drain.    -   4) Bind solution (H₂O (100 μL) is added. No drain!    -   5) Oligo dissolved in H₂O (max. 50 μL) is added. Shake 10 min        600 rpm, then drain.    -   6) H₂O is added (200 μL). Drain.    -   7) DMF (dry) is added (200 μL). Drain.    -   8) Repeat step 7 twice.    -   9) 0.5M mercaptoanisol and 0.25M DIPEA in DMF (dry) (200 μL;        freshly prepared) is added. Shake 24 h at 25° C., 600 rpm. No        drain!    -   10) 0.3 M AcOH in DMF is added (200 μL). Shake 5 min 600 rpm,        then drain.    -   11) DMF is added (200 μL). Drain.    -   12) Repeat step 11 twice    -   13) H₂O is added (200 μL). Drain.    -   14) Repeat step 13    -   15) Release solution is added (35 μL, 2M TEAB). Shake 10 min 600        rpm. Spin at 1000 g for 1 min, collect the solvent in an        eppendorf tube.    -   16) Repeat step 15.    -   17) Combine the solvents from step 14 and 15, then spin column        filtrate the sample.

Procedure for Ns Deprotection on DEAE Sepharose (Parallel Format)

-   -   1) 20 μL DEAE suspension is pipetted into each well and drained        by vacuum. (The capacity of the DEAE suspension is 0.5 nmol/μL        oligo use min 20 μL for >10 nmol oligo)    -   2) Add water (100 μL per well) and drain.    -   3) Bind solution (H₂O (100 μL per well)) is added. Shake 10 min        600 rpm, then drain.    -   4) Oligo dissolved in H₂O (max. 100 μL per well) is added. Shake        10 min 600 rpm, then drain.    -   5) H₂O is added (100 μL per well). Drain.    -   6) DMF (dry) is added (100 μL per well). Drain.    -   7) Repeat step 6 twice.    -   8) 0.5M mercaptoanisol and 0.25M DIPEA in DMF (dry) (100 μL per        well; freshly prepared) is added. Shake 24 h at 25° C., 600 rpm.        No drain!    -   9) 0.3 M AcOH in DMF is added (100 μL per well). Shake 5 min 600        rpm, then drain.    -   10) DMF is added (100 μL per well). Drain.    -   11) Repeat step 10 twice    -   12) H₂O is added (100 μL per well). Drain.    -   13) Repeat step 12    -   14) Release solution is added (50 μL per well, 2M TEAB). Shake        10 min 600 rpm. Spin at 1000 g for 1 min, collect the solvent in        a 96 well plate.    -   15) Repeat step 14.    -   16) Combine the solvents from step 14 and 15, then evaporate        samples to −50 μL per well and spin column filtrate the samples.

A reactant can include one or more functional groups in addition to thereactive group or groups employed to generate the molecule beingsynthesised by the methods of the present invention. One or more of thefunctional groups can be protected to prevent undesired reactions ofthese functional groups. Suitable protecting groups are known in the artfor a variety of functional groups (see e.g. Greene and Wuts, ProtectiveGroups in Organic Synthesis, second edition, New York: John Wiley andSons (1991), incorporated herein by reference). Useful protecting groupsinclude t-butyl esters and ethers, acetals, trityl ethers and amines,acetyl esters, trimethylsilyl ethers, trichloroethyl ethers and estersand carbamates.

The reactive groups of the reactants and/or the chemical reaction sitecan also be in a pro-form that has to be activated before a reactionwith (another) reactant can take place. As an example, the reactivegroups can be protected, c.f. above, with a suitable group, which needsto be removed before a reaction with the reactant can proceed.Accordingly, a reactant can comprise one or more reactive group(s) orprecursors of such groups, wherein the precursors can be activated orprocessed to generate the reactive group. Also, the reactant itself canbe a precursor for the structural entity which is going to beincorporated into the display molecule.

Examples of further protection groups include “N-protected amino” andrefers to protecting groups protecting an amino group againstundesirable reactions during synthetic procedures. Commonly usedN-protecting groups are disclosed in Greene, “Protective Groups InOrganic Synthesis,” (John Wiley & Sons, New York (1981)). PreferredN-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butyl-acetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), andbenzyloxycarbonyl (Cbz).

Also, the term “O-protected carboxy” refers to a carboxylic acidprotecting ester or amide group typically employed to block or protectthe carboxylic acid functionality while the reactions involving otherfunctional sites of the compound are performed. Carboxy protectinggroups are disclosed in Greene, “Protective Groups in Organic Synthesis”(1981). Additionally, a carboxy protecting group can be used as aprodrug whereby the carboxy protecting group can be readily cleaved invivo, for example by enzymatic hydrolysis, to release the biologicallyactive parent. Such carboxy protecting groups are well known to thoseskilled in the art, having been extensively used in the protection ofcarboxyl groups in the penicillin and cephalosporin fields as describedin U.S. Pat. Nos. 3,840,556 and 3,719,667.

In some embodiments, the reaction between reactants or between areactant and the chemical reaction site can involve a further reactant,such as a “bridging-molecule”, mediating a connection between thereactant and the chemical reaction site.

Scaffolds and Small Molecules

In some embodiments, the chemical reaction site comprises one or morescaffolds each having one or more reactive groups attached thereto. Theone or more reactive groups can e.g. be any of the groups cited hereinabove under the heading “Chemical reaction site and reactive groups”.

Examples of scaffold structures are e.g. benzodiazepines, steroids,hydantiones, piperasines, diketopiperasines, morpholines, tropanes,cumarines, qinolines, indoles, furans, pyrroles, oxazoles, amino acidprecursors, and thiazoles. Further examples are provided herein below.

When the synthesis methods employ scaffolds, a reactant comprising onlyone reactive group can be used in the end position of the scaffoldedmolecule being synthesised, whereas reactants comprising two or morereactive groups are suitably incorporated into the body part and/or abranching portion of a scaffolded molecule optionally capable of beingreacted with further reactants. Two or more reactive groups can bepresent on a scaffold having a core structure on which the molecule isbeing synthesised. This create the basis for synthesising multiplevariants of compounds of the same class or compounds sharing certainphysical or functional traits. The variants can be formed e.g. throughreaction of reactive groups of the scaffold with reactive groups of oneor more reactants, optionally mediated by fill-in groups (“bridgingmolecules”) and/or catalysts.

The small molecules of the compound libraries of the present inventioncan be linear, branched or cyclical, or comprise structural elementsselected from a combination of the aforementioned structures. Whencomprising a ring system, the small molecules can comprise a single ringor a fused ring system. One or more heteroatoms can be present in eitherthe single ring system or the fused ring system.

“Single ring” refers to a cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring having about three to about eight, or about four toabout six ring atoms. A single ring is not fused by being directlybonded at more than one ring atom to another closed ring.

“Fused ring” refers to fused aryl or cyclyl ring. For example, about sixor less, about five or less, about four or less, about three or less, orabout two rings can be fused. Each ring can be independently selectedfrom the group consisting of aryl, heteroaryl, cycloalkyl,heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl rings, each ofwhich ring may independently be substituted or unsubstituted, havingabout four to about ten, about four to about thirteen, or about four toabout fourteen ring atoms.

The number of rings in a small molecule refers to the number of singleor fused ring systems. Thus, for example a fused ring can be consideredto be one ring. As non-limiting examples, a phenyl ring, naphthalene,and norbornane, for purposes of the present invention, are allconsidered to be one ring, whereas biphenyl, which is not fused, isconsidered to be two rings.

A “heteroatom” refers to N, O, S, or P. In some embodiments, heteroatomrefers to N, O, or S, where indicated. Heteroatoms shall include anyoxidized form of nitrogen, sulfur, and phosphorus and the quaternizedform of any basic nitrogen.

Accordingly, examples of small molecule ring systems are:

“Aryl”, used alone or as part of a larger moiety as in “aralkyl”, refersto aromatic rings having six ring carbon atoms.

“Fused aryl,” refers to fused about two to about three aromatic ringshaving about six to about ten, about six to about thirteen, or about sixto about fourteen ring carbon atoms.

“Fused heteroaryl” refers to fused about two to about three heteroarylrings wherein at least one of the rings is a heteroaryl, having aboutfive to about ten, about five to about thirteen, or about five to aboutfourteen ring atoms.

“Fused cycloalkyl” refers to fused about two to about three cycloalkylrings having about four to about ten, about four to about thirteen, orabout four to about fourteen ring carbon atoms.

“Fused heterocycloalkyl” refers to fused about two to about threeheterocycloalkyl rings, wherein at least one of the rings is aheterocycloalkyl, having about four to about ten, about four to aboutthirteen, or about four to about fourteen ring atoms.

“Heterocycloalkyl” refers to cycloalkyls comprising one or moreheteroatoms in place of a ring carbon atom.

“Lower heterocycloalkyl” refers to cycloalkyl groups containing aboutthree to six ring members.

“Heterocycloalkenyl” refers to cycloalkenyls comprising one or moreheteroatoms in place of a ring carbon atom. “Lower heterocycloalkenyl”refers to cycloalkyl groups containing about three to about six ringmembers. The term “heterocycloalkenyl” does not refer to heteroaryls.

“Heteroaryl” refers to aromatic rings containing about three, aboutfive, about six, about seven, or about eight ring atoms, comprisingcarbon and one or more heteroatoms.

“Lower heteroaryl” refers to heteroaryls containing about three, aboutfive, or about six ring members.

Exemplary preferred scaffold structures can e.g. be selected from thegroup consisting of quinazoline, tricyclic quinazoline, purine,pyrimidine, phenylamine-pyrimidine, phthalazine, benzylidenemalononitrile, amino acid, tertiary amine, peptide, lactam, sultam,lactone, pyrrole, pyrrolidine, pyrrolinone, oxazole, isoxazole,oxazoline, isoxazoline, oxazolinone, isoxazolinone, thiazole,thiozolidinone, hydantoin, pyrazole, pyrazoline, pyrazolone, imidazole,imidazolidine, imidazolone, triazole, thiadiazole, oxadiazole,benzoffuran, isobenzofuran, dihydrobenzofuran, dihydroisobenzofuran,indole, indoline, benzoxazole, oxindole, indolizine, benzimidazole,benzimidazolone, pyridine, piperidine, piperidinone, pyrimidinone,piperazine, piperazinone, diketopiperazine, metathiazanone, morpholine,thiomorpholine, phenol, dihydropyran, quinoline, isoquinoline,quinolinone, isoquinolinone, quinolone, quinazolinone, quinoxalinone,benzopiperazinone, quinazolinedione, benzazepine and azepine.

Further exemplary scaffold structures linked to the displayoligonucleotides are selected from the group consisting of:

hydrido,substituted and unsubstituted alkyl, substituted and unsubstitutedhaloalkyl, substituted and unsubstituted hydroxyalkyl, substituted andunsubstituted alkylsulfonyl,substituted and unsubstituted alkenyl,halo,substituted and unsubstituted alkoxy, substituted and unsubstitutedalkoxyalkyl, substituted and unsubstituted haloalkoxy, substituted andunsubstituted haloalkoxyalkyl,substituted and unsubstituted aryl,substituted and unsubstituted heterocyclic,substituted and unsubstituted heteroaryl,sulfonyl, substituted and unsubstituted alkylsulfonyl, substituted andunsubstituted arylsulfonyl, sulfamyl, sulfonamidyl, aminosulfonyl,substituted and unsubstituted N-alkylaminosulfonyl, substituted andunsubstituted N-arylaminosulfonyl, substituted and unsubstitutedN,N-dialkylaminosulfonyl, substituted and unsubstitutedN-alkyl-N-arylaminosulfonyl, substituted and unsubstitutedN-alkylaminosulfonyl, substituted and unsubstitutedN,N-dialkylaminosulfonyl, substituted and unsubstitutedN-arylaminosulfonyl, substituted and unsubstitutedN-alkyl-N-arylaminosulfonyl,carboxy, substituted and unsubstituted carboxyalkyl,carbonyl, substituted and unsubstituted alkylcarbonyl, substituted andunsubstituted alkylcarbonylalkyl,substituted and unsubstituted alkoxycarbonyl, substituted andunsubstituted alkoxycarbonylalkyl,aminocarbonyl, substituted and unsubstituted aminocarbonylalkyl,substituted and unsubstituted N-alkylaminocarbonyl, substituted andunsubstituted N-arylaminocarbonyl, substituted and unsubstitutedN,N-dialkylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-arylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-hydroxyaminocarbonyl, substituted and unsubstitutedN-alkyl-N-hydroxyaminocarbonylalkyl, substituted and unsubstitutedN-alkylaminocarbonyl, substituted and unsubstitutedN,N-dialkylaminocarbonyl, substituted and unsubstitutedN-arylaminocarbonyl, substituted and unsubstitutedN-alkyl-N-arylaminocarbonyl, substituted and unsubstitutedaminocarbonylalkyl, substituted and unsubstitutedN-cycloalkylaminocarbonyl,substituted and unsubstituted aminoalkyl, substituted and unsubstitutedalkylaminoalkyl,amidino,cyanoamidino,substituted and unsubstituted heterocyclicalkyl,substituted and unsubstituted aralkyl,substituted and unsubstituted cycloalkyl,substituted and unsubstituted cycloalkenyl,substituted and unsubstituted alkylthio,substituted and unsubstituted alkylsulfinyl,substituted and unsubstituted N-alkylamino, substituted andunsubstituted N,N-dialkylamino,substituted and unsubstituted arylamino, substituted and unsubstitutedaralkylamino, substituted and unsubstituted N-alkyl-N-arylamino,substituted and unsubstituted N-aralkyl-N-alkylamino, substituted andunsubstituted N-arylaminoalkyl, substituted and unsubstitutedN-aralkylaminoalkyl, substituted and unsubstitutedN-alkyl-N-arylaminoalkyl, substituted and unsubstitutedN-aralkyl-N-alkylaminoalkyl,acyl, acylamino,substituted and unsubstituted arylthio, substituted and unsubstitutedaralkylthio,substituted and unsubstituted aryloxy, substituted and unsubstitutedaralkoxy,substituted and unsubstituted haloaralkyl,substituted and unsubstituted carboxyhaloalkyl,substituted and unsubstituted alkoxycarbonylhaloalkyl, substituted andunsubstituted aminocarbonylhaloalkyl, substituted and unsubstitutedalkylaminocarbonylhaloalkyl,substituted and unsubstituted alkoxycarbonylcyanoalkenyl,substituted and unsubstituted carboxyalkylaminocarbonyl,substituted and unsubstituted aralkoxycarbonylalkylaminocarbonyl,substituted and unsubstituted cycloalkylalkyl, andsubstituted and unsubstituted aralkenyl.

The same or different scaffolds comprising a plurality of sites forfunctionalization react with one or more identical or differentreactants in order to generate a compound library comprising differentsmall molecules. As used herein, the term “scaffold reactive group”refers to a chemical moiety that is capable of reacting with thereactive group of a reactant or chemical entity during the synthesis ifthe small molecule. Preferred scaffold reactive groups include, but arenot limited to, hydroxyl, carboxyl, amino, thiol, aldehyde, halogen,nitro, cyano, amido, urea, carbonate, carbamate, isocyanate, sulfone,sulfonate, sulfonamide, sulfoxide, amino acid, aryl, cycloalkyl,heterocyclyl, heteroaryl, etc. One of skill in the art will be aware ofother common functional groups that are encompassed by the presentinvention.

As used herein, the term “chemical entity reactive group” refers to achemical moiety of a reactant capable of reacting with one or morescaffold reactive groups. Preferred reactive groups of a reactantinclude, but are not limited to, hydroxyl, carboxyl, amino, thiol,aldehyde, halogen, nitro, cyano, amido, urea, carbonate, carbamate,isocyanate, sulfone, sulfonate, sulfonamide, sulfoxide, amino acid,aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. One of skill in the artwill be aware of other common functional groups that are encompassed bythe present invention.

The small molecule compounds of the present invention can be preparedusing a variety of synthetic reactions. Suitable reaction chemistriesare preferably selected from the following group: Amine acylation,reductive alkylation, aromatic reduction, aromatic acylation, aromaticcyclization, aryl-aryl coupling, [3+2]cycloaddition, Mitsunobu reaction,nucleophilic aromatic substitution, sulfonylation, aromatic halidedisplacement, Michael addition, Wittig reaction, Knoevenagelcondensation, reductive amination, Heck reaction, Stille reaction,Suzuki reaction, Aldol condensation, Claisen condensation, amino acidcoupling, amide bond formation, acetal formation, Diels-Alder reaction,[2+2]cycloaddition, enamine formation, esterification, Friedel Craftsreaction, glycosylation, Grignard reaction, Horner-Emmons reaction,hydrolysis, imine formation, metathesis reaction, nucleophilicsubstitution, oxidation, Pictet-Spengler reaction, Sonogashira reaction,thiazolidine formation, thiourea formation and urea formation.

Accordingly, the reactants and scaffolds of the present invention arethose that enable the reactions above to occur. These include, but arenot limited to, nucleophiles, electrophiles, acylating agents,aldehydes, carboxylic acids, alcohols, nitro, amino, carboxyl, aryl,heteroaryl, heterocyclyl, boronic acids, phosphorous ylides, etc. One ofskill in the art can envision other synthetic reactions and reactivecomponents useful in the present invention.

FIG. 58 highlights several reactions that can be used to prepare thesmall molecule compounds of the present invention, and the correspondingcoding reactions and reactive components. In FIG. 58, one of skill inthe art will understand that radicals R, R₁ and R₂ can be any of theabove described groups, such as, for example, hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl and heteroaryl, all optionallysubstituted as disclosed herein above. One of skill in the art willfurther understand that radical Ar is an aryl, which can be, forexample, phenyl, naphthyl, pyridyl and thienyl. In addition, one ofskill in the art will understand that radical X can be, for example,hydrogen, halogen alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

Contacting a scaffold with one or more reactants results in theconversion of the scaffold into a small molecule, or an intermediatescaffold structure to be further reacted or modified.

Accordingly, in one embodiment of the present invention, reactantscomprising one or more reactive groups, react with one or more,preferably more, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or from 10 to 20,reactive groups of a scaffold comprising a plurality of such reactivegroups, by one or more reactions selected from the group consisting ofamine acylation, reductive alkylation, aromatic reduction, aromaticacylation, aromatic cyclization, aryl-aryl coupling, [3+2]cycloaddition,Mitsunobu reaction, nucleophilic aromatic substitution, sulfonylation,aromatic halide displacement, Michael addition, Wittig reaction,Knoevenagel condensation, reductive amination, Heck reaction, Stillereaction, Suzuki reaction, Aldol condensation, Claisen condensation,amino acid coupling, amide bond formation, acetal formation, Diels-Alderreaction, [2+2]cycloaddition, enamine formation, esterification, FriedelCrafts reaction, glycosylation, Grignard reaction, Horner-Emmonsreaction, hydrolysis, imine formation, metathesis reaction, nucleophilicsubstitution, oxidation, Pictet-Spengler reaction, Sonogashira reaction,thiazolidine formation, thiourea formation and urea formation, whereinsaid scaffold preferably comprises a structural component selected fromthe group consisting of a cyclic or bicyclic hydrocarbon, a steroid, asugar, a heterocyclic structure, a polycyclic aromatic molecule, anamine, an amino acid, a multi-functional small molecule, a peptide or apolymer having various substituents at defined positions.

Suitable scaffolds of the present invention include, but are not limitedto, quinazoline, tricyclic quinazoline, purine, pyrimidine,phenylamine-pyrimidine, phthalazine, benzylidene malononitrile, aminoacid, tertiary amine, peptide, polymer, aromatic compounds containingortho-nitro fluoride(s), aromatic compounds containing para-nitrofluoride(s), aromatic compounds containing ortho-nitro chloromethyl,aromatic compounds containing ortho-nitro bromomethyl, lactam, sultam,lactone, pyrrole, pyrrolidine, pyrrolinone, oxazole, isoxazole,oxazoline, isoxazoline, oxazolinone, isoxazolinone, thiazole,thiozolidinone, hydantoin, pyrazole, pyrazoline, pyrazolone, imidazole,imidazolidine, imidazolone, triazole, thiadiazole, oxadiazole,benzofuran, isobenzofuran, dihydrobenzofuran, dihydroisobenzofuran,indole, indoline, benzoxazole, oxindole, indolizine, benzimidazole,benzimidazolone, pyridine, piperidine, piperidinone, pyrimidinone,piperazine, piperazinone, diketopiperazine, metathiazanone, morpholine,thiomorpholine, phenol, dihydropyran, quinoline, isoquinoline,quinolinone, isoquinolinone, quinolone, quinazolinone, quinoxalinone,benzopiperazinone, quinazolinedione, benzazepine and azepine, andwherein said scaffold preferably comprises at least two scaffoldreactive groups selected from the group consisting of hydroxyl,carboxyl, amino, thiol, aldehyde, halogen, nitro, cyano, amido, urea,carbonate, carbamate, isocyanate, sulfone, sulfonate, sulfonamide,sulfoxide, etc., for reaction with said one or more reactants.

The compound libraries can be partitioned or enriched with the selectionof possible “lead candidates” or “drug candidates” as a result. Theidentification of “lead candidates” or “drug candidates” typicallyresult when an association is formed between a small molecule member ofthe compound library and a target compound.

A “library” is a collection of library compounds, such as a collectionof different small molecules. The library can be virtual, in that it isan in silico or electronic collection of structures used forcomputational analysis as described herein. The library is preferablyphysical, in that the set of small molecules are synthesized, isolated,or purified.

A “lead candidate” is a library compound, such as a small molecule, thatbinds to a biological target molecule and is designed to modulate theactivity of a target protein. A lead candidate can be used to develop adrug candidate, or a drug to be used to treat a disorder or disease inan animal, including, for example, by interacting with a protein of saidanimal, or with a bacterial, viral, fungal, or other organism that canbe implicated in said animal disorder or disease, and that is selectedfor further testing either in cells, in animal models, or in the targetorganism. A lead candidate may also be used to develop compositions tomodulate plant diseases or disorders, including, for example, bymodulating plant protein activity, or by interacting with a bacterial,viral, fungal, or other organism implicated in said disease or disorder.

A “drug candidate” is a lead candidate that has biological activityagainst a biological target molecule and has ADMET (absorption,distribution, metabolism, excretion and toxicity) properties appropriatefor it to be evaluated in an animal, including a human, clinical studiesin a designated therapeutic application.

A “compound library” is a group comprising more than one compound, suchas more than one different small molecule, used for drug discovery. Thecompounds in the library can be small molecules designed to be linked toother compounds or small molecules, or the compounds can be smallmolecules designed to be used without linkage to other small molecules.

A “plurality” is more than one of whatever noun “plurality” modifies inthe sentence.

The term “obtain” refers to any method of obtaining, for example, asmall molecule, a library of such different small molecules, or a targetmolecule. The method used to obtain such compounds, biological targetmolecules, or libraries, may comprise synthesis, purchase, or any meansthe compounds, biological target molecules, or libraries can beobtained.

By “activity against” is meant that a compound may have binding activityby binding to a biological target molecule, or it may have an effect onthe enzymatic or other biological activity of a target, when present ina target activity assay. Biological activity and biochemical activityrefer to any in vivo or in vitro activity of a target biologicalmolecule. Non-limiting examples include the activity of a targetmolecule in an in vitro, cellular, or organism level assay. As anon-limiting example with an enzymatic protein as the target molecule,the activity includes at least the binding of the target molecule to oneor more substrates, the release of a product or reactant by the targetmolecule, or the overall catalytic activity of the target molecule.These activities can be accessed directly or indirectly in an in vitroor cell based assay, or alternatively in a phenotypic assay based on theeffect of the activity on an organism. As a further non-limiting examplewherein the target molecule is a kinase, the activity includes at leastthe binding of the kinase to its target polypeptide and/or othersubstrate (such as ATP as a non-limiting example) as well as the actualactivity of phosphorylating a target polypeptide.

Obtaining a crystal of a biological target molecule in association withor in interaction with a test small molecule includes any method ofobtaining a compound in a crystal, in association or interaction with atarget protein. This method includes soaking a crystal in a solution ofone or more potential compounds, or ligands, or incubating a targetprotein in the presence of one or more potential compounds, or ligands.

By “or” is meant one, or another member of a group, or more than onemember. For example, A, B, or C, may indicate any of the following: Aalone; B alone; C alone; A and B; B and C; A and C; A, B, and C.

“Association” refers to the status of two or more molecules that are inclose proximity to each other. The two molecules can be associatednon-covalently, for example, by hydrogen-bonding, van der Waals,electrostatic or hydrophobic interactions, or covalently.

“Active Site” refers to a site in a target protein that associates witha substrate for target protein activity. This site may include, forexample, residues involved in catalysis, as well as residues involved inbinding a substrate. Inhibitors may bind to the residues of the activesite.

“Binding site” refers to a region in a target protein, which, forexample, associates with a ligand such as a natural substrate,non-natural substrate, inhibitor, substrate analog, agonist orantagonist, protein, co-factor or small molecule, as well as,optionally, in addition, various ions or water, and/or has an internalcavity sufficient to bind a small molecule and can be used as a targetfor binding drugs. The term includes the active site but is not limitedthereby.

“Crystal” refers to a composition comprising a biological targetmolecule, including, for example, macromolecular drug receptor targets,including protein, including, for example, but not limited to,polypeptides, and nucleic acid targets, for example, but not limited to,DNA, RNA, and ribosomal subunits, and carbohydrate targets, for example,but not limited to, glycoproteins, crystalline form. The term “crystal”includes native crystals, and heavy-atom derivative crystals, as definedherein. The discussion below often uses a target protein as a exemplary,and non-limiting example. The discussion applies in an analogous mannerto all possible target molecules.

“Alkyl” and “alkoxy” used alone or as part of a larger moiety refers toboth straight and branched chains containing about one to about eightcarbon atoms. “Lower alkyl” and “lower alkoxy” refer to alkyl or alkoxygroups containing about one to about four carbon atoms.

“Cyclyl”, “cycloalkyl”, or “cycloalkenyl” refer to cyclic alkyl oralkenyl groups containing from about three to about eight carbon atoms.“Lower cyclyl,” “lower cycloalkyl.” or “lower cycloalkenyl” refer tocyclic groups containing from about three to about six carbon atoms.

“Alkenyl” and “alkynyl” used alone or as part of a larger moiety shallinclude both straight and branched chains containing about two to abouteight carbon atoms, with one or more unsaturated bonds between carbons.“Lower alkenyl” and “lower alkynyl” include alkenyl and alkynyl groupscontaining from about two to about five carbon atoms.

“Halogen” means F, Cl, Br, or I.

“Linker group” of a bifunctional complex means an organic moiety thatconnects two parts of the bifunctional complex, typically the smallmolecule and the oligonucleotide identifier. Linkers are typicallycomprised of an atom such as oxygen or sulfur, a unit such as —NH— or—CH₂—, or a chain of atoms, such as an alkylidene chain. The molecularmass of a linker is typically in the range of about 14 to about 200.Examples of linkers are known to those of ordinary skill in the art andinclude, but are not limited to, a saturated or unsaturated C₁₋₆alkylidene chain which is optionally substituted, and wherein up to twosaturated carbons of the chain are optionally replaced by —C(═O)—,—CONH—, CONHNH—, —CO₂—, —NHCO₂—, —O—, —NHCONH—, —O(C═O)—, —O(C═O)NH—,—NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or NHSO₂—.

An LogP value can be, for example, a calculated Log P value, forexample, one determined by a computer program for predicting Log P, thelog of the octanol-water partition coefficient commonly used as anempirical descriptor for predicting bioavailability (e.g. Lipinski'sRule of 5; Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.(1997) Experimental and computational approaches to estimate solubilityand permeability in drug discovery and development settings. Adv. DrugDelivery Rev. 23, 3-25). The calculated logP value may, for example, bethe SlogP value. SlogP is implemented in the MOE software suite fromChemical Computing Group, www.chemcomp.com. SlogP is based on an atomiccontribution model (Wildman, S. A., Crippen, G. M.; Prediction ofPhysicochemical Parameters by Atomic Contributions; J. Chem. Inf.Comput. Sci., 39(5), 868-873 (1999)).

Linker Moiety of a Bifunctional Complex

The nascent bifunctional complex comprising a chemical reaction site anda priming site for enzymatic addition of a tag can also comprise alinking moiety connecting the chemical reaction site and the primingsite.

In some embodiments it is preferable that the linker ensures that areactive group or a building block (reactant) or an encoded molecule isspaced away from the tag. In some embodiments it is also preferable thatthe linker ensures that a reactive group, a building block (reactant) oran encoded molecule can efficiently interact with another object such asa target used for screening/affinity selection.

The linker may be composed of one or more atoms. The linker may includemonomer units such as a peptide, protein, carbohydrates and substitutedcarbohydrates, a nucleotide, or any unit synthesized using organicand/or inorganic chemistry such as ethylenglycol; 1,3-propylenglycol;1,4-propylenglycol; 1,5-pentylenglycol. Any unit may be in substitutedform, e.g., 1,3.propylenglycol hydroxyl-substituted at the 2 position(Propane-1,2,3-triol). The linker may also include a polymer such as anorganic polymer, e.g. a polyethylenglycol, a polypeptide, or anoligonucleotide, polyvinyl, acetylene or polyacetylene, aryl/hetaryl andsubstituted aryl/hetaryl, ethers and polyethers such as e.g.polyethylenglycol and substituted polyethers, amines, polyamines andsubstituted polyamines, single- or double-stranded oligonucleotides, andpolyamides and natural and unnatural polypeptides. The linker maycontain any combination of monomeric and polymeric units. The linker mayalso contain branching units. The linker may be flexible or rigid andcontain flexible and/or rigid parts. The linker may be attached to oneor more reactive groups by one or more atoms. Moreover, the linker maycontain one or more reactive groups. The linker may be attached to thetag via one or more atoms, e.g. via a phosphate group.

The attachment point may be anywhere on the tags such as a 5′ or 3′phosphate, a 5′ or 3′ OH, carbon, oxygen or nitrogen on one or morenucleotides. The linker may be attached one or more tags such as bothstrands of a double stranded tag. The linker may be attached to the tagby one or more covalent bonds and/or one or more noncovalent bonds, e.g.the linker may include a biotin moiety which can bind noncovalently to astreptavidin molecule attached to the tag. Preferably the length of thelinker is in the range of 1-50 angstrom, more preferably 5-30 angstrom,most preferably 10-25 angstrom. Preferably, the linker separates thelinker-tag attachment point from a reactive group by 5-50 atomic bonds,more preferably, by 10-30 atomic bonds, most preferably by 15-25 atomicbonds. Preferably, the linker is prepared fromDiisopropyl-phosphoramidous acid 2-cyano-ethyl ester2-[2-(2-{2-[2-(2-{[(4-methoxy-phenyl)-diphenyl-methyl]-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethylester or similar compound. Preferably, the linker contains the structure2-[2-(2-{2-[2-(2-Amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethanol.

Cleavable linkers can be cleaved in any number of ways, e.g., byphotolysis or increased temperature, or by the addition of acid, base,enzymes, ribozymes, other catalysts, or any other agents.

To maintain a physical link between the identifier and the encodedmolecule (in the case of stage 2 synthesis, the template and the encodedmolecule), at least one non-cleavable linker is needed. Thenon-cleavable linker may of course be cleavable under certainconditions, but is non-cleavable under the conditions that lead to thebi-functional molecule employed in the screening. This non-cleavablelinker is preferably flexible, enabling it to expose the encodedmolecule in an optimal way.

Under certain conditions it may desirable to be able to cleave thelinker before, during or after the screening of the library has beendone, for example in order to perform a mass spectrometric analysis ofthe encoded molecule without the identifier attached, or to performother types of assays on the free encoded molecule.

The linking moiety in one embodiment separates the priming site from thechemical reaction site so as to allow an enzyme to perform the tagaddition and provide for a hybridisation region. The linking moiety canbe a nucleic acid sequence, such as an oligonucleotide. The length ofthe oligonucleotide is preferably suitable for hybridisation with acomplementing oligonucleotide, i.e. the number of nucleotides in thelinking moiety is suitably 2 or more, such as 3 or more, for example 4or above, such as 5 or more, for example 6 or more, such as 7 or more,for example 8 or more nucleotides.

In a certain embodiment, the linking moiety is attached to the chemicalreaction site via a spacer comprising a selectively cleavable linker toenable release of the molecule from the identifier oligonucleotide in astep subsequent to the formation of the final bifunctional complex. Thecleavable linker can be selectively cleavable, i.e. conditions can beselected that only cleave that particular linker.

The cleavable linkers can be selected from a variety chemicalstructures. Examples of linkers includes, but are not limited to,linkers having an enzymatic cleavage site, linkers comprising a chemicaldegradable component, linkers cleavable by electromagnetic radiation.

Examples of Linkers Cleavable by Electromagnetic Radiation (Light)

o-nitrobenzyl

p-alkoxy

o-nitrobenzyl in Exo Position

For more details see Holmes C P. J. Org. Chem. 1997, 62, 2370-2380

3-nitrophenyloxy

For more details see Rajasekharan Pillai, V. N. Synthesis. 1980, 1-26

Dansyl Derivatives:

For more details see Rajasekharan Pillai, V. N. Synthesis. 1980, 1-26

Coumarin Derivatives

For more details see R. O, Schoenleber, B. Giese. Synlett 2003, 501-504

R¹ and R² can be any molecule or chemical entity (CE) such as thoseexemplified herein above under section A (acylation reactions),respectively. Moreover, R¹ and R² can be either the target or a solidsupport, respectively. R³ can be e.g. H or OCH₃ independently of R¹ andR². If X is O then the product will be a carboxylic acid. If X is NH theproduct will be a carboxamide

One specific example is the PC Spacer Phosphoramidite (Glen researchcatalog #10-4913-90) which can be introduced in an oligonucleotideduring synthesis and cleaved by subjecting the sample in water to UVlight (˜300-350 nm) for 30 seconds to 1 minute.

DMT=4,4′-Dimethoxytrityl

iPr=Isopropyl

CNEt=Cyanoethyl

The above PC spacer phosphoamidite is suitable incorporated in a libraryof complexes at a position between the identifier and the potential drugcandidate. The spacer can be cleaved according to the followingreaction.

R¹ and R² can be any molecule or chemical entity (CE) such as thoseexemplified herein above under section A (acylation reactions).Moreover, R¹ and R² can be either the target or a solid support,respectively. In a preferred aspect R² is an oligonucleotide identifierand the R¹ is the molecule. When the linker is cleaved a phosphate groupis generated allowing for further biological reactions. As an example,the phosphate group can be positioned in the 5′ end of anoligonucleotide allowing for an enzymatic ligation process to takeplace.

Examples of Linkers Cleavable by Chemical Agents:

Ester linkers can be cleaved by nucleophilic attack using e.g. hydroxideions. In practice this can be accomplished by subjecting thetarget-ligand complex to a base for a short period.

R¹ and R² can be the either of be the potential drug candidate or theidentifier, respectively. R⁴⁻⁶ can be any of the following: H, CN, F,NO₂, SO₂NR₂.

Disulfide linkers can efficiently be cleaved/reduced by Tris(2-carboxyethyl) phosphine (TCEP). TCEP selectively and completelyreduces even the most stable water-soluble alkyl disulfides over a widepH range. These reductions frequently required less than 5 minutes atroom temperature. TCEP is a non-volatile and odorless reductant andunlike most other reducing agents, it is resistant to air oxidation.Trialkylphosphines such as TCEP are stable in aqueous solution,selectively reduce disulfide bonds, and are essentially unreactivetoward other functional groups commonly found in proteins.

More details on the reduction of disulfide bonds can be found in Kirley,T. L. (1989), Reduction and fluorescent labeling ofcyst(e)ine-containing proteins for subsequent structural analysis, Anal.Biochem. 180, 231 and Levison, M. E., et al. (1969), Reduction ofbiological substances by water-soluble phosphines: Gamma-globulin.Experentia 25, 126-127.

Linkers Cleavable by Enzymes

The linker connecting the potential drug candidate with the identifieror the solid support and the target can include a peptide region thatallows a specific cleavage using a protease. This is a well-knownstrategy in molecular biology. Site-specific proteases and their cognatetarget amino acid sequences are often used to remove the fusion proteintags that facilitate enhanced expression, solubility, secretion orpurification of the fusion protein.

Various proteases can be used to accomplish a specific cleavage. Thespecificity is especially important when the cleavage site is presentedtogether with other sequences such as for example the fusion proteins.Various conditions have been optimized in order to enhance the cleavageefficiency and control the specificity. These conditions are availableand know in the art.

Enterokinase is one example of an enzyme (serine protease) that cut aspecific amino acid sequence. Enterokinase recognition site isAsp-Asp-Asp-Asp-Lys (DDDDK), and it cleaves C-terminally of Lys.Purified recombinant Enterokinase is commercially available and ishighly active over wide ranges in pH (pH 4.5-9.5) and temperature (4-45°C.).

The nuclear inclusion protease from tobacco etch virus (TEV) is anothercommercially available and well-characterized proteases that can be usedto cut at a specific amino acid sequence. TEV protease cleaves thesequence Glu-Asn-Leu-Tyr-Phe-Gln-Gly/Ser (ENLYFQG/S) between Gln-Gly orGln-Ser with high specificity.

Another well-known protease is thrombin that specifically cleaves thesequence Leu-Val-Pro-Arg-Gly-Ser (LVPAGS) between Arg-Gly. Thrombin hasalso been used for cleavage of recombinant fusion proteins. Othersequences can also be used for thrombin cleavage; these sequences aremore or less specific and more or less efficiently cleaved by thrombin.Thrombin is a highly active protease and various reaction conditions areknown to the public.

Activated coagulation factor FX (FXa) is also known to be a specific anduseful protease. This enzyme cleaves C-terminal of Arg at the sequenceIle-Glu-Gly-Arg (IEGR). FXa is frequently used to cut between fusionproteins when producing proteins with recombinant technology. Otherrecognition sequences can also be used for FXa.

Other types of proteolytic enzymes can also be used that recognizespecific amino acid sequences. In addition, proteolytic enzymes thatcleave amino acid sequences in an un-specific manner can also be used ifonly the linker contains an amino acid sequence in the complex molecule.

Other type of molecules such as ribozymes, catalytically activeantibodies, or lipases can also be used. The only prerequisite is thatthe catalytically active molecule can cleave the specific structure usedas the linker, or as a part of the linker, that connects the encodingregion and the displayed molecule or, in the alternative the solidsupport and the target. Also, a variety of endonucleases are availablethat recognize and cleave a double stranded nucleic acid having aspecific sequence of nucleotides.

Molecules

A molecule can be formed by the reaction of one or more reactive groupson one or more reactants or a molecule can be formed by the reaction ofone or more reactive groups on one or more reactants and one or morechemical reaction sites.

A molecule can comprise one or more atoms and one or more bonds, whereinsuch bonds between atoms may optionally be single bonds, double bonds ortriple bonds and a combination thereof, wherein such atoms may comprisecarbon, silicon, nitrogen, phosphorous, oxygen, sulfur, selenium,fluorine, chlorine, bromine, iodine, borane, stannane, lithium, sodium,potassium, kalium, calcium, barium, strontium, including any combinationthereof. In further embodiments, a molecule may comprise other atoms inthe periodic system.

In one or more embodiments, a reactive group may comprise one or moreatoms and one or more bonds, wherein such bonds between atoms mayoptionally be single bonds, double bonds or triple bonds and acombination thereof, wherein such atoms may comprise carbon, silicon,nitrogen, phosphorous, oxygen, sulfur, selenium, fluorine, chlorine,bromine, iodine, borane, stannane, lithium, sodium, potassium, kalium,calcium, barium, strontium. In further embodiments, a molecule maycomprise other atoms in the periodic system.

In one or more embodiments, a chemical reaction site may comprise one ormore atoms and one or more bonds, wherein such bonds between atoms mayoptionally be single bonds, double bonds or triple bonds and acombination thereof, wherein such atoms may comprise carbon, silicon,nitrogen, phosphorous, oxygen, sulfur, selenium, fluorine, chlorine,bromine, iodine, borane, stannane, lithium, sodium, potassium, kalium,calcium, barium, strontium. In further embodiments, a molecule maycomprise other atoms in the periodic system.

In one or more embodiments, the molecule comprisings the molecule, whichcan be formed following the reaction of one or more reactants with oneor more chemical reaction sites, where the molecule is linked through alinker to a display oligonucleotide optionally covalently linked to oneor more tags.

In one or more embodiments, the molecule comprisings the chemical motifformed by reaction of reactive groups comprising atoms participating inthe reaction between one or more reactive groups on one or morereactants and one or more chemical reaction sites.

In one embodiment, the molecule comprisings a carboxamide. In anotherembodiment, the molecule comprisings a sulfonamide. In a furtherembodiment, the molecule comprisings a urea group. In furtherembodiments, the molecule comprisings an amine. In another embodiment,the molecule comprisings an ether. In a further embodiment, the moleculecomprisings an ester for example an carboxylic acid ester. In a furtherembodiment, the molecule comprisings an alkene. In a further embodiment,the molecule comprisings an alkyne. In a further embodiment, themolecule comprisings an alkane. In a further embodiment, the moleculecomprisings a thioether. In a further embodiment, the moleculecomprisings a sulfone. In a further embodiment, the molecule comprisingsa sulfoxide. In a further embodiment, the molecule comprisings asulfonamide. In a further embodiment, the molecule comprisings acarbamate. In a further embodiment, the molecule comprisings acarbonate. In a further embodiment, the molecule comprisings a 1,2-diol.In a further embodiment, the molecule comprisings a 1,2-dioxoalkane. Ina further embodiment, the molecule comprisings a ketone. In a furtherembodiment, the molecule comprisings an imine. In a further embodiment,the molecule comprisings a hydrazone. In a further embodiment, themolecule comprisings an oxime. In a further embodiment, the moleculecomprisings an aminohetarene.

In one embodiment the molecule comprising a cyclic structure such as a3-40 member ring, such as for example an 18-40 member ring, such as forexample a 3-7 member ring, for example an 8-24 member ring, for examplean 8-18 member ring, for example an 8-14 member ring, for example a 5-7member ring, such as for example a 3 member ring, for example a 4 memberring, for example a 5 member ring, for example a 6 member ring, forexample a 7 member ring, for example an 8 member ring, for example a 9member ring, for example a 10 member ring, for example an 11 memberring, for example a 12 member ring, for example a 13 member ring, forexample a 14 member ring, for example a 15 member ring, for example a 16member ring, for example a 17 member ring, for example an 18 memberring.

In one embodiment the molecule comprisings a cyclic structure, forexample an aliphatic ring, for example an aromatic ring, for example apartially unsaturated ring and a combination thereof.

In one embodiment the molecule comprising a 3 member ring comprising oneor more carbon ring atoms and optionally one or more heteroatoms, forexample one or more oxygen ring atoms, for example one or more nitrogenring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 4 member ring comprising oneor more carbon ring atoms and optionally one or more heteroatoms, forexample one or more oxygen ring atoms, for example one or more nitrogenring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 5 member ring comprising oneor more carbon ring atoms and optionally one or more heteroatoms, forexample one or more oxygen ring atoms, for example one or more nitrogenring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 6 member ring comprising oneor more carbon ring atoms and optionally one or more heteroatoms, forexample one or more oxygen ring atoms, for example one or more nitrogenring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 7 member ring comprising oneor more carbon ring atoms and optionally one or more heteroatoms, forexample one or more oxygen ring atoms, for example one or more nitrogenring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising an 8 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 9 member ring comprising oneor more carbon ring atoms and optionally one or more heteroatoms, forexample one or more oxygen ring atoms, for example one or more nitrogenring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 10 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising an 11 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 12 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 13 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 14 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 15 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 16 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising a 17 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment the molecule comprising an 18 member ring comprisingone or more carbon ring atoms and optionally one or more heteroatoms,for example one or more oxygen ring atoms, for example one or morenitrogen ring atoms, for example one or more sulfur ring atoms.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a pyrrole, a tetrahydrofuran, a tetrahydropyran, a furan, athiophene, a pyrazole, an imidazole, a furazan, an oxazole, anisoxazole, a thiazole, an isothiazole, a 1,2,3-triazole, a1,2,4-triazole, an 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,a tetrazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine, apiperidine, a piperazine, a morpholine, a thiomorpholine, an indole, anisoindole, an indazole, a purine, an indolizine, a purine, a quinoline,an isoquinoline, a quinazoline, a pteridine, a quinolizine, a carbazole,a phenazine, a phenothiazine, a phenanthridine, a chroman an oxolane, adioxine, an aziridine, an oxirane, an azetidine, an azepine, which mayoptionally be substituted by one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a benzopyrrole, a benzotetrahydrofuran, abenzotetrahydropyran, a benzofuran, a benzothiophene, a benzopyrazole,an benzoimidazole, a benzofurazan, an benzooxazole, an benzoisoxazole, abenzothiazole, an benzoisothiazole, a benzo1,2,3-triazole, abenzopyridine, a benzopyridazine, a benzopyrimidine, a benzopyrazine, abenzopiperidine, a benzopiperazine, a benzomorpholine, abenzothiomorpholine, an benzoindole, an benzoisoindole, anbenzoindazole, an benzoindolizine, a benzoquinoline, abenzoisoquinoline, a benzoquinazoline, a benzopteridine, abenzoquinolizine, a benzocarbazole, a benzophenazine, abenzophenothiazine, a benzophenanthridine, a benzochroman anbenzooxolane, a benzodioxine, a benzoazetidine, a benzoazepine, whichmay optionally be substituted by one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a pyridopyrrole, a pyridotetrahydrofuran, apyridotetrahydropyran, a pyridofuran, a pyridothiophene, apyridopyrazole, an pyridoimidazole, a pyridofurazan, an pyridooxazole,an pyridoisoxazole, a pyridothiazole, an pyridoisothiazole, apyrido1,2,3-triazole, a pyridopyridine, a pyridopyridazine, apyridopyrimidine, a pyridopyrazine, a pyridopiperidine, apyridopiperazine, a pyridomorpholine, a pyridothiomorpholine, anpyridoindole, an pyridoisoindole, an pyridoindazole, anpyridoindolizine, a pyridoquinoline, a pyridoisoquinoline, apyridoquinazoline, a pyridopteridine, a pyridoquinolizine, apyridocarbazole, a pyridophenazine, a pyridophenothiazine, apyridophenanthridine, a pyridochroman an pyridooxolane, a pyridodioxine,a pyridoazetidine, a pyridoazepine, which may optionally be substitutedby one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a pyrrolopyrrole, a pyrrolotetrahydrofuran, apyrrolotetrahydropyran, a pyrrolofuran, a pyrrolothiophene, apyrrolopyrazole, an pyrroloimidazole, a pyrrolofurazan, anpyrrolooxazole, an pyrroloisoxazole, a pyrrolothiazole, anpyrroloisothiazole, a pyrrolo1,2,3-triazole, a pyrrolopyridine, apyrrolopyridazine, a pyrrolopyrimidine, a pyrrolopyrazine, apyrrolopiperidine, a pyrrolopiperazine, a pyrrolomorpholine, apyrrolothiomorpholine, an pyrroloindole, an pyrroloisoindole, anpyrroloindazole, an pyrroloindolizine, a pyrroloquinoline, apyrroloisoquinoline, a pyrroloquinazoline, a pyrrolopteridine, apyrroloquinolizine, a pyrrolocarbazole, a pyrrolophenazine, apyrrolophenothiazine, a pyrrolophenanthridine, a pyrrolochroman anpyrrolooxolane, a pyrrolodioxine, a pyrroloazetidine, a pyrroloazepine,which may optionally be substituted by one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a furopyrrole, a furotetrahydrofuran, afurotetrahydropyran, a furofuran, a furothiophene, a furopyrazole, anfuroimidazole, a furofurazan, an furooxazole, an furoisoxazole, afurothiazole, an furoisothiazole, a furo1,2,3-triazole, a furopyridine,a furopyridazine, a furopyrimidine, a furopyrazine, a furopiperidine, afuropiperazine, a furomorpholine, a furothiomorpholine, an furoindole,an furoisoindole, an furoindazole, an furoindolizine, a furoquinoline, afuroisoquinoline, a furoquinazoline, a furopteridine, a furoquinolizine,a furocarbazole, a furophenazine, a furophenothiazine, afurophenanthridine, a furochroman an furooxolane, a furodioxine, afuroazetidine, a furoazepine, which may optionally be substituted by oneor more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a thienopyrrole, a thienotetrahydrofuran, athienotetrahydropyran, a thienofuran, a thienothiophene, athienopyrazole, an thienoimidazole, a thienofurazan, an thienooxazole,an thienoisoxazole, a thienothiazole, an thienoisothiazole, athieno1,2,3-triazole, a thienopyridine, a thienopyridazine, athienopyrimidine, a thienopyrazine, a thienopiperidine, athienopiperazine, a thienomorpholine, a thienothiomorpholine, anthienoindole, an thienoisoindole, an thienoindazole, anthienoindolizine, a thienoquinoline, a thienoisoquinoline, athienoquinazoline, a thienopteridine, a thienoquinolizine, athienocarbazole, a thienophenazine, a thienophenothiazine, athienophenanthridine, a thienochroman an thienooxolane, a thienodioxine,a thienoazetidine, a thienoazepine, which may optionally be substitutedby one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a imidazopyrrole, a imidazotetrahydrofuran, aimidazotetrahydropyran, a imidazofuran, a imidazothiophene, aimidazopyrazole, an imidazoimidazole, a imidazofurazan, animidazooxazole, an imidazoisoxazole, a imidazothiazole, animidazoisothiazole, a imidazo,2,3-triazole, a imidazopyridine, aimidazopyridazine, a imidazopyrimidine, a imidazopyrazine, aimidazopiperidine, a imidazopiperazine, a imidazomorpholine, aimidazothiomorpholine, an imidazoindole, an imidazoisoindole, animidazoindazole, an imidazoindolizine, a imidazoquinoline, aimidazoisoquinoline, a imidazoquinazoline, a imidazopteridine, aimidazoquinolizine, a imidazocarbazole, a imidazophenazine, aimidazophenothiazine, a imidazophenanthridine, a imidazochroman animidazooxolane, a imidazodioxine, a imidazoazetidine, a imidazoazepine,which may optionally be substituted by one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a pyrazolopyrrole, a pyrazolotetrahydrofuran, apyrazolotetrahydropyran, a pyrazolofuran, a pyrazolothiophene, apyrazolopyrazole, an pyrazoloimidazole, a pyrazolofurazan, anpyrazolooxazole, an pyrazoloisoxazole, a pyrazolothiazole, anpyrazoloisothiazole, a pyrazolo-1,2,3-triazole, a pyrazolopyridine, apyrazolopyridazine, a pyrazolopyrimidine, a pyrazolopyrazine, apyrazolopiperidine, a pyrazolopiperazine, a pyrazolomorpholine, apyrazolothiomorpholine, an pyrazoloindole, an pyrazoloisoindole, anpyrazoloindazole, an pyrazoloindolizine, a pyrazoloquinoline, apyrazoloisoquinoline, a pyrazoloquinazoline, a pyrazolopteridine, apyrazoloquinolizine, a pyrazolocarbazole, a pyrazolophenazine, apyrazolophenothiazine, a pyrazolophenanthridine, a pyrazolochroman anpyrazolooxolane, a pyrazolodioxine, a pyrazoloazetidine, apyrazoloazepine, which may optionally be substituted by one or moresubstituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a oxazolopyrrole, a oxazolotetrahydrofuran, aoxazolotetrahydropyran, a oxazolofuran, a oxazolothiophene, aoxazolopyrazole, an oxazoloimidazole, a oxazolofurazan, anoxazolooxazole, an oxazoloisoxazole, a oxazolothiazole, anoxazoloisothiazole, a oxazolo1,2,3-triazole, a oxazolopyridine, aoxazolopyridazine, a oxazolopyrimidine, a oxazolopyrazine, aoxazolopiperidine, a oxazolopiperazine, a oxazolomorpholine, aoxazolothiomorpholine, an oxazoloindole, an oxazoloisoindole, anoxazoloindazole, an oxazoloindolizine, a oxazoloquinoline, aoxazoloisoquinoline, a oxazoloquinazoline, a oxazolopteridine, aoxazoloquinolizine, a oxazolocarbazole, a oxazolophenazine, aoxazolophenothiazine, a oxazolophenanthridine, a oxazolochroman anoxazolooxolane, a oxazolodioxine, a oxazoloazetidine, a oxazoloazepine,which may optionally be substituted by one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a isoxazolopyrrole, a isoxazolotetrahydrofuran, aisoxazolotetrahydropyran, a isoxazolofuran, a isoxazolothiophene, aisoxazolopyrazole, an isoxazoloimidazole, a isoxazolofurazan, anisoxazolooxazole, an isoxazoloisoxazole, a isoxazolothiazole, anisoxazoloisothiazole, a isoxazolo1,2,3-triazole, a isoxazolopyridine, aisoxazolopyridazine, a isoxazolopyrimidine, a isoxazolopyrazine, aisoxazolopiperidine, a isoxazolopiperazine, a isoxazolomorpholine, aisoxazolothiomorpholine, an isoxazoloindole, an isoxazoloisoindole, anisoxazoloindazole, an isoxazoloindolizine, a isoxazoloquinoline, aisoxazoloisoquinoline, a isoxazoloquinazoline, a isoxazolopteridine, aisoxazoloquinolizine, a isoxazolocarbazole, a isoxazolophenazine, aisoxazolophenothiazine, a isoxazolophenanthridine, a isoxazolochroman anisoxazolooxolane, a isoxazolodioxine, a isoxazoloazetidine, aisoxazoloazepine, which may optionally be substituted by one or moresubstituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a thiaazolopyrrole, a thiaazolotetrahydrofuran, athiaazolotetrahydropyran, a thiaazolofuran, a thiaazolothiophene, athiaazolopyrazole, an thiaazoloimidazole, a thiaazolofurazan, anthiaazolooxazole, an thiaazoloisoxazole, a thiaazolothiazole, anthiaazoloisothiazole, a thiaazolo1,2,3-triazole, a thiaazolopyridine, athiaazolopyridazine, a thiaazolopyrimidine, a thiaazolopyrazine, athiaazolopiperidine, a thiaazolopiperazine, a thiaazolomorpholine, athiaazolothiomorpholine, an thiaazoloindole, an thiaazoloisoindole, anthiaazoloindazole, an thiaazoloindolizine, a thiaazoloquinoline, athiaazoloisoquinoline, a thiaazoloquinazoline, a thiaazolopteridine, athiaazoloquinolizine, a thiaazolocarbazole, a thiaazolophenazine, athiaazolophenothiazine, a thiaazolophenanthridine, a thiaazolochroman anthiaazolooxolane, a thiaazolodioxine, a thiaazoloazetidine, athiaazoloazepine, which may optionally be substituted by one or moresubstituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a isothiaazolopyrrole, a isothiaazolotetrahydrofuran, aisothiaazolotetrahydropyran, a isothiaazolofuran, aisothiaazolothiophene, a isothiaazolopyrazole, an isothiaazoloimidazole,a isothiaazolofurazan, an isothiaazolooxazole, an isothiaazoloisoxazole,a isothiaazolothiazole, an isothiaazoloisothiazole, aisothiaazolo1,2,3-triazole, a isothiaazolopyridine, aisothiaazolopyridazine, a isothiaazolopyrimidine, aisothiaazolopyrazine, a isothiaazolopiperidine, aisothiaazolopiperazine, a isothiaazolomorpholine, aisothiaazolothiomorpholine, an isothiaazoloindole, anisothiaazoloisoindole, an isothiaazoloindazole, anisothiaazoloindolizine, a isothiaazoloquinoline, aisothiaazoloisoquinoline, a isothiaazoloquinazoline, aisothiaazolopteridine, a isothiaazoloquinolizine, aisothiaazolocarbazole, a isothiaazolophenazine, aisothiaazolophenothiazine, a isothiaazolophenanthridine, aisothiaazolochroman an isothiaazolooxolane, a isothiaazolodioxine, aisothiaazoloazetidine, a isothiaazoloazepine, which may optionally besubstituted by one or more substituents.

In one embodiment a molecule comprises for example a fully unsaturatedring structure, for example a fully saturated ring structure, forexample a partly saturated ring structure, wherein such ring structuremay comprise a isothiaazolopyridine, a isothiaazolopyridazine, aisothiaazolopyrimidine, a isothiaazolopyrazine, a isothiazolotriazine, apyrimidinopyridine, a pyrimidinopyridazine, a pyrimidinopyrimidine, apyrimidinopyrazine, a pyrimidinotriazine, a pyrazinopyridine, apyrazinopyridazine, a pyrazinopyrimidine, a pyrazinopyrazine, apyrazinotriazine, a pyridazinopyridine, a pyridazinopyridazine, apyridazinopyrimidine, a pyridazinopyrazine, a pyridazinotriazine, atriazinopyridine, a triazinopyridazine, a triazinopyrimidine, atriazinopyrazine, a triazinotriazine, which may optionally besubstituted by one or more substituents.

In one embodiment the molecule may comprising a lactone, a lactam, a2-hydroxy tetrahydrofuran, a 2-alkoxy tetrahydrofuran, a 2-hydroxytetrahydropyran, a 2-alkoxy tetrahydropyran, a benzene, a naphthalene, aphenanthrene, an anthracene, a cyclopentane, a cyclopentene, acyclohexane, a cyclohexene, a 1,3-cyclohexadiene, a 1,4-cyclohexadiene,a cyclopentadiene, which may optionally be substituted by one or moresubstituents.

In one embodiment the molecule may comprising a monocyclic system, abicyclic system, a tricyclic system, a spirocyclic system, a fusedbicyclic system, wherein such cyclic systems may optionally comprisecarbon atoms, silicon atoms, nitrogen atoms, phosphorous atoms, oxygenatoms, sulfur atoms, wherein such cyclic systems may optionally besubstituted by one or more substituents.

In a further embodiment, two or more cyclic structures may optionally belinked by one or more bonds comprising single bonds, double bonds,triple bonds and a combination thereof, wherein such cyclic systems mayoptionally comprise carbon atoms, silicon atoms, nitrogen atoms,phosphorous atoms, oxygen atoms, sulfur atoms, wherein such cyclicsystems may optionally be substituted by one or more substituents.

Resynthesis of Bifunctional Complexes

In some embodiments unique bifunctional complexes are resynthesizedfollowing synthesis and analysis of a library. The unique bifunctionalcomplexes may be identified by unique codon sequences. It is thenpossible to mix the bifunctional complexes and then enrich certainbifunctional complexes according to e.g. affinity for a target, e.g. byperforming an affinity selection. Such enriched bifunctional complexescan then be identified e.g. by quantitative PCR, hybridization or asimilar method.

Also provided in the present invention is a method to obtain informationon display molecules in their free form, i.e. without an identifieroligonucleotide. A display molecule can be synthesized from an initialnascent bifunctional complex with a cleavable linker. The identifier ortag of this complex may have any composition, e.g. it may be anoligonucleotide of any length or sequence, for example an oligonucleotide of 10-40 nucleotides in length. During synthesis the nascentbifunctional complex can be purified by gel filtration (size exclusion)because the mass of the tag employed, e.g. from 3000 to 12000 daltonallows separation of the nascent bifunctional complex from reactants,buffer components and other molecular entities of small mass, whichtypically have masses less than 1000 dalton. Furthermore, the use of anoligonucleotide tag allows the amount of material retained duringsynthesis of the bifunctional complex to be estimated by measuring e.g.the optical density (OD) of the DNA by measuring absorbance at 260 nm.Alternatively, an oligonucleotide tag with an easily measurable labelsuch as phosphor-32 or fluorescent groups is used. Following synthesisand subsequent purification of the bifunctional complex, the cleavablelinker is cleaved e.g. by electromagnetic radiation, whereby the displaymolecule is released. The tag can then be removed from the solutioncontaining the display molecule, e.g. by hybridizing the tag to acomplementary anti-tag oligonucleotide attached to a solid phase whichcan easily be removed from the solution. The display molecule can thenbe used in any assay determining some property of the display moleculesuch as Ki determination versus an enzyme, Kd determination versus aprotein or other target, or determination of any in vitro or biologicalparameter such as the activated partial thromboplastin time (aPTT).Removal of the tag is advantageous if the assay used to measure someproperty of the display molecule is sensitive to the presence of DNA.One advantage of the describe method is that the synthesis scale is onthe order of nanomoles. Only a small amount of each building block(reactant) used to synthesize the bifunctional complex is thereforerequired. Also the building blocks (reactants) used to synthesize thedisplay molecule may be labelled by any method e.g. by radioactiveatoms; for example the display molecule may be synthesized using on ormore building blocks (reactants) containing a hydrogen-3 or carbon-14atom. In this way a released display molecule may be used in an assaywhich measures some property of the display molecule by measuring theamount of label present. For example, the display molecule may beapplied on one side of a layer of confluent CaCo-2 cells. Following aperiod of incubation the presence of label (reflecting the presence ofdisplay molecule) may be measured at each side of the confluent celllayer. Said measurements can be informative of the bioavailability ofthe display molecule. In another example the display molecule is appliedto plasma proteins, e.g. human plasma proteins and the fraction ofdisplay molecule bound to plasma protein can be determined.

Library Synthesis and Further Processing Steps

When a library of different bifunctional complexes are synthesised,split-and-mix synthesis methods are employed. A plurality of nascentbifunctional complexes obtained after a first synthesis round aredivided (“split”) into multiple fractions. In each fraction, the nascentbifunctional complex is reacted sequentially or simultaneously with adifferent reactant and a corresponding oligonucleotide tag whichidentifies each different reactant.

The molecules (linked to their respective identifier oligonucleotides)produced in each of the fractions as disclosed herein above and in claim1, are combined (“pooled”) and then divided again into multiplefractions. Each of these fractions is then reacted with a further unique(fraction-specific) reactant and a further oligonucleotide tagidentifying the reactant. The number of unique molecules present in theproduct library is a function of the number of different reactants usedin each round of the synthesis and the number of times the pooling anddividing process is repeated.

When a library of different bifunctional complexes are synthesised, themethod comprises the steps of providing in separate compartments nascentbifunctional complexes, each comprising a chemical reaction site and apriming site for enzymatic addition of a tag, and performing in anyorder reaction in each compartment between the chemical reaction siteand one or more reactants, and enzymatically adding the priming site oneor more tags identifying the one or more reactants having participatedin the synthesis of a molecule or an intermediate thereof.

The nascent bifunctional complexes in each compartment can be identicalor different. In the event the nascent bifunctional complex differs atthe chemical reaction site, the nascent bifunctional complex suitablycomprises a tag identifying the structure of the chemical reaction site.Similar, the reactants applied in each compartment can be identical ordifferent as the case may be. Also, the reaction conditions in eachcompartment can be similar or different.

Accordingly, the contents of any two or more compartments can be mixedand subsequently split into an array of compartments for a new round ofreaction. Thus, in any round subsequent to the first round, the endproduct of a preceding round of reaction is used as the nascentbifunctional complex to obtain a library of bifunctional complexes, inwhich each member of the library comprises a reagent specific reactionproduct and respective tags which codes for the identity of each of thereactants that have participated in the formation of the reactionproduct.

In some embodiments, it is preferred to add the tag to the nascentbifunctional complex prior to the reaction, because it can be preferableto apply conditions for the reaction which are different form theconditions used by the enzyme. Generally, enzyme reactions are conductedin aqueous media, whereas the reaction between the reactant and thechemical reaction site for certain reactions is favoured by an organicsolvent. An appropriate approach to obtain suitable condition for bothreactions is to conduct the enzyme reaction in an aqueous media,lyophilize and subsequent dissolve or disperse in a media suitable ofthe reaction at the chemical reactive site to take place. In analternative approach, the lyophilization step can be dispensed with asthe appropriate reaction condition can be obtained by adding a solventto the aqueous media. The solvent can be miscible with the aqueous mediato produce a homogeneous reaction media or immiscible to produce abi-phasic media.

Libraries of the present invention can be virtual libraries, in thatthey are collections of computational or electronic representations ofmolecules. The libraries may also be “wet” or physical libraries, inthat they are collection of molecules that are actually obtainedthrough, for example, synthesis or purification, or they can be acombination of wet and virtual, with some of the molecules having beenobtained and others remaining virtual, or both.

Libraries of the present invention may, for example, comprise at leastabout 10, at least about 50, at least about 100, at least about 500, atleast about 750, at least about 1,000, or at least about 2,500 moleculesor compounds.

Libraries of the present invention may also include subsets of largerlibraries, i.e. enriched libraries comprising at least two members of alarger (naïve) library.

In various embodiments, at least about 40%, at least about 50%, at leastabout 75%, at least about 90%, or at least about 95% of the molecules ofthe libraries of the present invention have less than six, less thanfive, or, for example, less than four hydrogen bond acceptors.

In various embodiments, at least about 40%, at least about 50%, at leastabout 75%, at least about 90%, or at least about 95% of the molecules ofthe libraries of the present invention have less than six, less thanfive, or, for example, less than four hydrogen bond donors.

In various embodiments, at least about 40%, at least about 50%, at leastabout 75%, at least about 90%, or at least about 95% of the molecules orcompounds of the libraries of the present invention have a calculatedLogP value of less than six, less than five, or, for example, less thanfour.

In various embodiments, at least about 40%, at least about 50%, at leastabout 75%, at least about 90%, or at least about 95% of the molecules orcompounds of the libraries of the present invention have a molecularweight of less than about 500, such as less than about 350, for example,less than about 300, less than about 250, or less than about 200Daltons.

Also included in the scope of the present invention are methods andcomputer processor executable instructions on one or more computerreadable storage devices wherein the instructions cause representationand/or manipulation, via a computer output device, of a molecule libraryof the present invention. Also, methods for performing suchrepresentation and/or manipulation of a molecule library having beenproduced by the methods of the present invention are within the scope ofthe present invention.

For example, the processor executable instructions are provided on oneor more computer readable storage devices wherein the instructions causerepresentation and/or manipulation, via a computer output device, of alibrary of the present invention, such as, for example, a library ofscaffolded molecules, the library may comprise a plurality of molecules,wherein each molecule comprises a scaffolded part and one or morechemical entities.

The present invention also provides processor executable instructions onone or more computer readable storage devices wherein the instructionscause representation and/or manipulation, via a computer output device,of a combination of structures for analysis, wherein the combinationcomprises the structure of one or more members of a library of thepresent invention, and a biological target molecule.

In one embodiment of the invention the structure of the one or moremembers of the library can be represented or displayed as interactingwith at least a portion of a substrate binding pocket structure of abiological target molecule. The processor executable instructions mayoptionally include one or more instructions directing the retrieval ofdata from a computer readable storage medium for the representationand/or manipulation of a structure or structures described herein.

In another aspect of the invention, combinations are provided. Forexample, provided in the present invention is a combination ofstructures for analysis, comprising a molecule library of the presentinvention, and a biological target molecule, wherein the structurescomprise members of the library, the target molecule, and combinationsthereof.

Also provided in the present invention is a combination of structuresfor analysis, comprising a member of a molecule library of the presentinvention and a biological target molecule, wherein the structurescomprise the library member, the biological target molecule, andcombinations thereof. The combination can be virtual, for example,computational representations, or actual or wet, for example, physicalentities. In one example, at least one member of the library binds to aportion of a ligand binding site of the target molecule. In some aspectsof the combination, the concentration ratio of library members to targetmolecules is in a ratio of, for example about 50,000, about 25,000,about 10,000, about 1,000, about 100, or about 10 mol/mol. In someaspects of the combination, the concentration of library members isclose to, at, or beyond the solubility point of the solution.

The present invention also provides a mixture for analysis by x-raycrystallography, comprising a plurality of molecules or compoundsselected from a library of the present invention and a biological targetmolecule. The biological target molecule, may, for example, be aprotein, or a nucleic acid. The biological target molecule may, forexample, be crystalline.

Methods of designing novel compounds or lead candidates are alsoprovided in the present invention. For example, in one embodiment of thepresent invention, a method is provided of designing a lead candidatehaving activity against a biological target molecule, comprisingobtaining a library of the present invention, determining the structuresof one or more, and in some embodiments of the invention at least two,members of the library in association with the biological targetmolecule, and selecting information from the structures to design atleast one lead candidate.

The method can further comprise the step of determining the structure ofthe lead candidate in association with the biological target molecule.In one embodiment, the method further comprises the step of designing atleast one second library of compounds wherein each compound of thesecond library comprises a scaffold and two or more chemical entities;and each compound of the second library is different. In one embodimentof the invention, the scaffold of the compounds of the second libraryand the scaffold of the lead candidate is the same. In one embodiment,the method further comprises the steps of obtaining the second library;and determining the structures of one or more, and in some embodimentsof the invention at least two, compounds of the second library inassociation with the biological target molecule. The biological targetmolecule can be, for example, a protein or, for example, a nucleic acid.The biological target molecule may, for example, be crystalline.

The method can, for example, comprise preparing a plurality of mixturesof the biological target molecule with at least one of the molecules.The method can also, for example, comprise preparing a mixture of thebiological target molecule with a plurality of the molecules.

The method can, for example, further comprise the step of assaying thebiological activity of one or more, and in some embodiments of theinvention at least two, molecules against the biological targetmolecule. The assay may, for example, be a biochemical activity assay,or, for example, a biophysical assay, such as, for example, a bindingassay, including, for example, but not limited to, an assay thatcomprises the use of mass spectroscopy. The biological activity assaymay, for example, be conducted before, after, or simultaneously withobtaining the structure of the molecule in association with thebiological target molecule.

In one example, a subset of the molecules or compounds assayed in thebiological activity assay are selected for the structure determinationstep. In another example, a subset of the molecules or compounds used inthe structure determination step are assayed in the biological activityassay. In one embodiment of the invention, the structure is determinedusing a method comprising X-ray crystallography. In one example, themethod can further comprise the step of analyzing the binding of one ormore, and in some embodiments of the invention at least two, moleculesto the biological target molecule using a computational method.

In another example, the method can further comprise the steps ofselecting or otherwise using information about the structures to designat least one second library, wherein the second library is derived fromat least one molecule of the molecule library; and comprises compoundshaving modifications in at least one of the chemical entities of thescaffolded molecule. The method can, for example, further comprise thestep of assaying the biological activity of one or more, and in someembodiments of the invention at least two, of the compounds against thebiological target molecule.

The present invention also provides a method of designing a leadcandidate having activity against a biological target molecule,comprising obtaining a library of bifunctional complexes of the presentinvention, determining the structures of at least one compound of thelibrary in association with the biological target molecule, andselecting information from the structure to design at least one leadcandidate.

The present invention also comprises methods where the molecule librarycan be screened against a first biological target molecule andeventually developed for activity against a second biological molecule.In some aspects of the invention, molecules or compounds found to haveactivity toward one biological target molecule can be screened againstother biological target molecules where they may, for example, have thesame or even enhanced activity. The second biological target moleculemay, for example, be a related protein, and may, for example, be fromthe same protein family, for example, a protease, phosphatase, nuclearhormone receptor, or kinase family.

Thus, provided in the present invention is a method of designing acandidate compound having activity against a second biological targetmolecule, comprising obtaining a lead candidate of the presentinvention, determining the interaction of the lead candidate with asecond biological target molecule; and designing at least one secondlibrary of compounds wherein each compound of the second librarycomprises a scaffold found in the lead candidate and modifications in atleast one of the chemical entities on the scaffold.

In other methods of the invention, the molecule libraries are used inbinding or biological activity assays before crystallization, and thosemolecules or compounds exhibiting a certain threshold of activity areselected for crystallization and structure determination. The binding oractivity assay may also be performed at the same time as, or after,crystallization. Because of the ability to determine any complexstructure, the threshold for determining whether a particular moleculeis a hit can be set to be more inclusive than traditional highthroughput screening assays, because obtaining a large number of falsepositives would not greatly negatively affect the process. For example,weak binders from a binding assay can be used in crystallization, andany false-positives easily weeded out. In other methods of theinvention, the binding or biological activity assays can be performedafter crystallization, and the information obtained, along with thestructural data, used to determine the direction of the follow-upcombinatorial library.

In one embodiment of the present invention, derivative compounds areselected from each library, wherein each such library comprisesmolecules with modifications at one chemical entity, resulting in aderived substituent, and for each library, the chemical entity that ismodified is a different chemical entity, a new derivative compound isselected having the best-scoring chemical entities in one compound. Thisselected derivative compound can be used as the basis of a new round oflibrary design and screening, or can be the basis of a more traditionalcombinatorial library. The selected derivative compound may also besubjected to computational elaboration, in that it may serve as thebasis for the individual design of an improved compound for screening.The cycle continues until a new derivative compound is obtained that canbe considered to be a lead compound, having a desired IC₅₀, and otherdesirable lead compound properties.

The present invention also provides methods for designing the moleculeand compound libraries of the present invention. Provided in the presentinvention is a method of designing a molecule library for drugdiscovery, comprising screening or reviewing a list of syntheticallyaccessible or commercially available molecules, and selecting moleculesfor the library wherein each of the molecules comprises: two or morechemical entities and preferably less than 25 non-hydrogen atoms. Themolecules of the library may, for example, comprise, in their scaffold,at least one single or fused ring system. The molecules of the librarymay, for example, comprise in their scaffold at least one hetero atom onat least one ring system.

Also provided in the present invention is a method of screening for amolecule for use as a base molecule for library design, comprisingobtaining a library of the present invention, screening the library formembers having binding activity against a biological target molecule;and selecting a molecule of member (s) with binding activity to use as abase molecule for library design.

Also provided in the present invention are lead candidates and candidatecompounds obtained by the methods of the present invention, librariesobtained by the methods of the present invention, and librariescomprising compounds with molecules selected by the methods of thepresent invention.

The present invention also provides a method of designing a leadcandidate having biophysical or biochemical activity against abiological target molecule, comprising obtaining the structure of thebiological target molecule bound to a molecule, wherein the moleculecomprises a substituent having anomalous dispersion properties,synthesizing a lead candidate molecule comprising the step of replacinga chemical entity or derived substituent on the compound with asubstituent comprising a functionalized carbon, nitrogen, oxygen,sulfur, or phosphorus atom, and assaying the lead candidate molecule forbiophysical or biochemical activity against the biological targetmolecule.

The present invention also provides a method of designing a leadcandidate having biophysical or biochemical activity against abiological target molecule, comprising combining a biological targetmolecule with a mixture comprising one or more, and in some embodimentsof the invention at least two, molecules or compounds, wherein at leastone of the molecules or compounds comprises a substituent havinganomalous dispersion properties, identifying a molecule bound to thebiological target molecule using the anomalous dispersion properties ofthe substituent, synthesizing a lead candidate molecule comprising thestep of replacing the anomalous dispersion substituent with asubstituent comprising a functionalized carbon or nitrogen atom, andassaying the lead candidate molecule for biophysical or biochemicalactivity against the biological target molecule.

Design of Libraries

A vast number of different libraries may be designed that can besynthesized by methods of the present invention. The library may bedesigned using a number of approaches known to a person skilled in theart. Library design (i.e. the choice of reactants, linker, and tagswhich shall be used for the synthesis of a library) may consist of anumber of steps including but not limited to:

-   -   I. Choosing the linker type, e.g., the linker may be chosen to        have a single chemical reaction site, two chemical reaction        sites or more. The chemical reaction site may be chosen to be an        amine, an acid, an aldehyde or a C—X group where X is a halogen.    -   II. Choosing the number of reactants to be used at each cycle        during library synthesis    -   III. Choosing the type of reactants such as        -   a. reactants with a single reactive group such as a —COOH            group, an amine, an isocyanate, a sulfonyl halogen, an            aldehyde or a C—X group where X is a halogen, and/or        -   b. reactants with two reactive groups chosen from the group            of a —COOH group, an amine, an isocyanate, a sulfonyl            halogen, an aldehyde or a C—X group where X is a halogen,            and/or        -   c. reactants with three reactive groups chosen from the            group of a —COOH group, an amine, an isocyanate, a sulfonyl            halogen, an aldehyde or a C—X group where X is a halogen.        -   d. reactants with four reactive groups chosen from the group            of a —COOH group, an amine, an isocyanate, a sulfonyl            halogen, an aldehyde or a C—X group where X is a halogen.        -   e. reactants with five reactive groups chosen from the group            of a —COOH group, an amine, an isocyanate, a sulfonyl            halogen, an aldehyde or a C—X group where X is a halogen.        -   f. reactants with six reactive groups chosen from the group            of a —COOH group, an amine, an isocyanate, a sulfonyl            halogen, an aldehyde or a C—X group where X is a halogen.        -   g. All or some of the reactive group may be appropriately            protected using a protection group known to a person skilled            in the art such as an fmoc group, a nosyl group, an msec            group, a boc group or a tBu group (see general procedures            for details).    -   IV. Choosing the number of each type of reactants to be used at        each cycle during library synthesis.    -   V. Analyzing reactants with regards to properties such as        molecular weight, octanol/water and water/gas log Ps, log S, log        BB, overall CNS activity, Caco-2 and MDCK cell permeabilities,        human oral absorption, log Khsa for human serum albumin binding,        and log IC50 for HERG K+-channel blockage logD, number of        hydrogen bond donors or acceptors, rotational bonds, polar        surface area, Lipinski Rule-of-Five violations, drug-likeness or        lead-likeness etc. Said properties may be predicted e.g. using a        computer program such as qikprop (www.schrodinger.com) or        determined in an assay by a person skilled in the art.    -   VI. Comparing reactants with other reagents with regards to        structural of functional similarity    -   VII. Enumerating the library to be synthesized, i.e., virtually        (e.g. using a computer) constructing all possible encoded        molecules.        -   a. Analyzing said molecules with regards to properties such            as molecular weight, octanol/water and water/gas log Ps, log            S, log BB, overall CNS activity, Caco-2 and MDCK cell            permeabilities, human oral absorption, log Khsa for human            serum albumin binding, and log IC50 for HERG K+-channel            blockage logD, number of hydrogen bond donors or acceptors,            rotational bonds, polar surface area, Lipinski Rule-of-Five            violations, drug-likeness or lead-likeness etc. Said            properties may be predicted e.g. using a computer program            such as qikprop (www.schrodinger.com) or determined in an            assay by a person skilled in the art.        -   b. Comparing said molecules with other molecules with            regards to structural of functional similarity    -   VIII. Testing the reaction efficiency of reactants before using        them for library synthesis.    -   IX. Generating one or more encoded molecules using reactants        from an initial list of reactants to be used for the synthesis        of a specific library, subjecting said encoded molecule(s) to        one or more assays, and adjusting said list of reactants (i.e.        removing reactants from the list or adding reactants to the        list) based on the results of said assays.    -   X. Choosing reactants based on prior information regarding a        target or a related molecule on which a library is intended to        be screened. The related molecule may be one or more parts of a        target, a molecule derived from a target e.g. by mutation, a        molecule which is related to the target e.g. another member of        the target family, a target homolog etc. Said prior information        may be        -   a. structural information obtained by x-ray crystallography            or NMR or another method        -   b. structural information obtained by x-ray crystallography            or NMR or another method in the presence of ligand and/or            cofactor        -   c. structural information obtained by x-ray crystallography            or NMR or another method in the presence of a molecule or            fragment such as a reactant or a reactant analog        -   d. information obtained by mutagenesis followed by an assay            which can be performed by a person skilled in the art.        -   e. structure-activity information obtained e.g. by synthesis            of a series of molecules followed by testing of the            molecules in an appropriate assay. Such information may            suggest reactants which are identical or similar to parts of            said tested molecules.    -   XI. Choosing reactants based on prior information obtained by        synthesis of a library followed by screening of the library and        analyses of the screening results. Said library being        synthesized by the methods described by the current invention or        related methods for synthesizing bifunctional molecules such but        not limited to those described in Rasmussen (2006) WO        06/053571A2, Liu et al. (2002), WO 02/074929 A2; Pedersen et        al. (2002) WO 02/103008 A2; Pedersen et al. (2003) WO03/078625        A2; Harbury and Halpin, WO 00/23458, and Hansen et al WO        06/048025.

In some embodiments it is preferred that each display molecule has thesame general structure. In other embodiments it is preferred thatdisplay molecules may have different general structures, e.g. becomposed from a different number of chemical entities:

First reactant Second reactant Third reactant

Fourth reactant Fifth reactant Final product

This can be achieved e.g. by subjecting to library to a final reactantreaction step. The reactant can only react with display molecules thathave a corresponding reactive group. Thus, the finalized library maycontain display molecules of different general structures, e.g., becomposed of a different number of entities.

Preferred Split-and-Mix Methods

In preferred embodiments there are provided methods for preparing alarge combinatorial library of compounds which has the advantages of (i)massive parallel synthesis of subunits and known, addressable librarypositions, (ii) adaptable to virtually any oligomer or small-moleculechemistry, (iii) a relatively large area for synthesis of each librarymember, (iv) capable of being screened either as a mixture or asindividual library compounds in either solution phase or solid phase,and (v) capable of amplifying and modifying selected library compounds.

The principle advantage of the below-disclosed embodiments is that thetag directs and encodes the synthesis of the compound to which it iscovalently attached (not merely reporting on the synthetic history ofindividual compounds), the tag can be used to create librarysubpopulations based on hybridization, the types of compounds that aresynthesized are not limited to polypeptides and polynucleotides, thenumber of compounds that can be produced far exceeds that of traditionalcombinatorial libraries and the tag comprises or consists of a nucleicacid molecule which can be amplified biochemically and improved bygenetic recombination, and in vitro evolution. The nucleic acid moleculecan comprise any of the nucleotides disclosed herein above.

In one aspect of the present invention, the below disclosed split-n-mixmethods are carried out subsequently to the above-disclosed methods forobtaining a bifunctional complex comprising a molecule and an identifieroligonucleotide, wherein, initially, a nascent bifunctional complexcomprising one or more chemical reaction site(s) and one or more primingsite(s) for enzymatic addition of a tag is reacted, in any order, a) atthe chemical reaction site with one or more reactant(s) in the form ofreactants or chemical entities and b) reacted at the priming site withone or more identifier oligonucleotide tag(s) identifying thereactant(s) which have reacted—or are going to react—with each otherand/or with the chemical reaction site, wherein tag ligation results inthe formation only of a single stranded identifier oligonucleotidecomprising a plurality of tags, whereas no anti-tag at least partlyhybridised the one or more tags are ligated to a neighbouring anti-tag.Subsequently to this method, the below disclosed embodiments are carriedout, optionally after having selected desirable bifunctional complexesfrom the first synthesis method, and further optionally after havingamplified the identifier oligonucleotide of one or more of said selectedbifunctional complexes. The amplification can be carried out when theidentifier oligonucleotide is attached to the molecule of thebifunctional complex, or the amplification can occur after theidentifier oligonucleotide has been released from the remaining part ofthe bifunctional complex.

Accordingly, in one embodiment there is provided further method stepsand compositions for further iterative synthesis and further screeningof a plurality of compounds wherein a nucleic acid tag directs andencodes the synthesis of the compound to which it is covalentlyattached, and the tag is a DNA molecule which can be amplifiedbiochemically.

The further methods of the present invention provide for synthesis of aplurality of compounds in a combinatorial library by way of a split andcombine synthesis strategy, wherein synthesis is directed by the nucleicacid tag. The library can be provided in solution or attached to a solidsupport.

The nucleic acid tags useful in the methods of the present inventioncomprise nucleic acid sequences having a plurality of different firsthybridization sequences, a mixture of different second hybridizationsequences, and a chemical reaction site.

The present invention further provides a library of nucleic acid tags,also termed nucleic acid supports for use in directing the synthesis ofa plurality of compounds wherein each tag has a first segment having aselected one of a plurality of different first hybridization sequences,a mixture of different second hybridization sequences, and a chemicalreaction site; and a second segment having a selected one of a pluralityof different second hybridization sequences and a mixture of differentfirst hybridization sequences.

The further methods of the present invention provide subsets of nucleicacid tags generated by base-specific duplex formation between eachdifferent first or second hybridization sequence and a complementaryoligonucleotides or oligonucleotide analogs. The chemical reaction sitesin each of the subsets are reacted with a selected reagent to form areagent-specific compound intermediate.

The further methods of the present invention also provide that the stepsof formation of subsets of nucleic acid sequences by base-specificduplex formation be repeated and a chemical subunit added to thechemical reaction site or last added chemical subunit within each subsetuntil synthesis of the plurality of compounds is complete.

In an exemplary aspect of the present invention, the nucleic acid tagsinclude alternating spacer and hybridization sequences, wherein thespacer sequences are the same for all subsets of nucleic acid sequencesand the hybridization sequences are different for each subset of nucleicacid sequences.

In a related aspect, the spacer sequence portion of each nucleic acidsequence has a restriction enzyme site which is unique to a given spacersequence.

The methods of the present invention provide for the synthesis of smallmolecules with different chemical sequences, catalysts useful for thesynthesis of complex molecules from simple substrates, inorganiccompounds with useful properties as materials, non-ribosomally producedpolypeptides, peptoids, polyketide-based natural products or subunitoligomers, e.g., polypeptides, polynucleotides etc. as disclosed hereinabove.

In one embodiment, the invention provides compound libraries wherein thecompounds of such libraries can be subjected to enrichment for one ormore desired activities on a continuously amplifying population.

In the methods of the present invention compounds having one or moredesired activities are enriched to yield a subpopulation of nucleic acidsequences. The enriched subpopulation (s) of nucleic acid sequencesserve as the starting material for repeating the step-wise synthesis ofadditional compounds.

Alternatively, the enriched subpopulation of nucleic acid sequences isamplified by nonspecific polymerase chain reaction (PCR), and a newchemical reaction site added prior to repeating the step-wise synthesisof additional compounds.

A process termed “polynucleotide or gene shuffling” may also be appliedto the present invention. In such a process, the enriched subpopulationof nucleic acid sequences is treated with one or more restrictionenzymes under conditions effective to produce a partial digest bycleavage at a sequence-specific restriction enzyme site within eachspacer sequence. The partially digested nucleic acid sequences arerejoined and a new chemical reaction site added prior to repeating thestep-wise synthesis of additional compounds.

Compound libraries which are synthesized under the direction ofcompound-specific synthesis-directing nucleic acid tags are alsoprovided by the present invention. In this aspect, the nucleic acidsequences which direct the synthesis of the compounds can be subjectedto genetic recombination or in vitro evolution by repeated cycles ofenrichment and step-wise synthesis; enrichment, PCR amplification andstep-wise synthesis; or enrichment, partial digestion, rejoining offragments and stepwise synthesis to yield a highly enrichedsubpopulation of synthesis-directing nucleic acid sequences.

Preferably, subpopulations of enriched compounds are produced by themethods of the present invention by selecting for activities whichinclude, but are not limited to, modulation of enzymatic activity,modulation of non-enzymatic catalytic activity, modulation ofprotein-protein interactions and modulation of receptor/ligandinteractions, etc.

The invention also provides a method for library splitting on the basisof sequence hybridization post-synthesis. In this aspect, a completelibrary is synthesized, split by hybridization based on the differentsequence directing nucleic acid tag attached to each library member andfurther step performed on the split library.

The invention also provides a method for library splitting on the basisof sequence hybridization following enrichment of certain bifunctionalcomplexes, e.g. by affinity selection. In this aspect, a completelibrary is synthesized, subjected to affinity selection and split byhybridization based on the different sequence directing nucleic acid tagattached to each library member. Then further steps may be performed onthe split library such as decoding tags of individual split librarypools by sequencing.

Preferred types of compounds in the compound libraries of the presentinvention include, but are not limited to, small molecules withdifferent chemical sequences, catalysts useful for the synthesis ofcomplex molecules from simple substrates, inorganic compounds withuseful properties as materials, non-ribosomally produced polypeptides,peptoids, polyketide-based natural products or subunit oligomers, e.g.,polypeptides, polynucleotides etc.

Further, the invention provides a method to perform all geneticmanipulations possible with natural biopolymers (through themanipulation of DNA instructions) on such DNAtemplated combinatoriallibraries of compounds as a means to provide a method to identify usefulcompounds from large combinatorial libraries of compounds, as describedabove.

These and other objects and features of the invention will become morefully apparent when the following detailed description of the inventionis read in conjunction with the accompanying drawings.

Definitions

The term “combinatorial library” is defined herein to mean a library ofmolecules containing a large number, typically between 10e3 and at least10e6, such as 10e8, for example 10e10 different compounds typicallycharacterized by different sequences of subunits, or a combination ofdifferent sequences of side chains and linkages.

The term “combinatorial library of subunit oligomers” is defined hereinto mean a set of oligomers containing substantially each sequencepermutation that can be formed by placing a selected one of a number ofdifferent subunits at each of a selected number of residue positions.

“Different-sequence oligomer compounds” are oligomers, such asoligonucleotides, oligonucleotide analogs, oligopeptides, oligopeptideanalogs, oligosaccharides, or lipopeptides with different permutationsof lipid and/or sequences in the peptide moieties, glycopeptides withdifferent sequence permutations in the saccharide and/or peptidemoieties, non-biological oligomers with different-sequence permutations,or different-substituent compounds in a small molecule library.

The terms “base-specific duplex formation” or “specific hybridization”refer to temperature, ionic strength and/or solvent conditions effectiveto produce sequence-specific pairing between a single-strandedoligonucleotide and its complementary-sequence nucleic acid strand, fora given length oligonucleotide. Such conditions are preferably stringentenough to prevent or largely prevent hybridization of twonearly-complementary strands that have one or more internal basemismatches. Preferably the region of identity between two sequence sforming a base-specific duplex is greater than about 5 bp, morepreferably the region of identity is greater than 10 bp.

The terms “polymerase chain reaction” and “PCR” refer to a process ofamplifying one or more specific nucleic acid sequences, wherein (i)oligonucleotide primers which determine the ends of the sequences to beamplified are annealed to single-stranded nucleic acids in a testsample, (ii) a nucleic acid polymerase extends the 3′ ends of theannealed primers to create a nucleic acid strand complementary insequence to the nucleic acid to which the primers were annealed, (iii)the resulting double-stranded nucleic acid is denatured to yield twosingle-stranded nucleic acids, and (iv) the processes of primerannealing, primer extension, and product denaturation are repeatedenough times to generate easily identified and measured amounts of thesequences defined by the primers. The sequential annealing, extensionand denaturation steps are controlled by varying the temperature of thereaction container, normally in a repeating cyclical manner. Annealingand extension are typically carried out between 40-80 C, whereasdenaturation requires temperatures between about 80 and 100 C. A“thermal cycler”, such as Perkin Elmer Model 9600, is typically used toregulate the reactions.

The terms “oligonucleotides” or “oligos” as used herein refer to nucleicacid oligomers containing between about 3 and typically up to about 150,such as from about 5 to about 100 nucleic acid subunits, for examplefrom about 5 to about 80 nucleic acid subunits. In the context of oligoswhich direct the synthesis of the library compounds of the presentinvention, the oligos may include or be composed primarily of nucleotideanalog subunits, or other subunits capable of forming sequence-specificWatson-Crick base pairing, when assembled in a linear polymer, with theproviso that the free ends of the oligos are ribonucleotide ordeoxyribonucleotide subunits capable of providing a suitable substratefor strand-directed polymerization in the presence of a DNA polymeraseand one or more nucleotide triphosphates, e.g., conventionaldeoxyribonucleotides with free 3′OH groups. A “known sequence oligo” isan oligo whose nucleic acid sequence is known.

The term “oligonucleotide analog” is defined herein to mean a nucleicacid that has been modified and which is capable of some or all of thechemical or biological activities of the oligonucleotide from which itwas derived. An oligonucleotide analog will generally containphosphodiester bonds, although in some cases, oligonucleotide analogsare included that may have alternate backbones. (See, E. G., severalnucleic acid analogs described in Rawls, C & E News, Jun. 2, 1997, page35). Modifications of the ribose-phosphate backbone may facilitate theaddition of additional moieties such as labels, or can be done toincrease the stability and half-life of such molecules. In addition,mixtures of naturally occurring nucleic acids and analogs can be made.Alternatively, mixtures of different nucleic acid analogs, and mixturesof naturally occurring nucleic acids and analogs can be made. Theoligonucleotides can be single stranded or double stranded, asspecified, or contain portions of both double stranded or singlestranded sequence. The oligonucleotide can be DNA, RNA or a hybrid,where the nucleic acid contains any combination of deoxyribo- andribo-nucleotides, and any combination of bases, including uracil,adenine, thymine, cytosine, guanine, inosine, xathanine hypoxathanine,isocytosine, isoguanine, etc.

The “subunit oligomers” produced by the methods of the present inventiontypically have 3 to 20 residue positions at which the subunit assumesone of a plurality of possible forms, e.g., different nucleic acid oramino acid side chains.

“Different-sequence small-molecule compounds” are small organicmolecules, typically, but not necessarily, having a common parentstructure, such as a ring structure, and a plurality of different Rgroup substituents or ring-structure modifications, each of which takesa variety of forms, e.g., different R groups. Such compounds are usuallynon-oligomeric (that is, do not consist of sequences of repeatingsimilar subunits) and can be similar in terms of basic structure andfunctional groups, but vary in such aspects as chain length, ring sizeor number, or patterns of substitution.

The term “chemical reaction site” as used herein refers to a chemicalcomponent capable of forming a variety of chemical bonds including, butnot limited to; amide, ester, urea, urethane, carbon-carbonyl bonds,carbon-nitrogen bonds, carbon-carbon single bonds, olefin bonds,thioether bonds, and disulfide bonds.

The terms “nucleic acid tag” and “nucleic acid support” are definedherein to mean the nucleic acid sequences which comprise a plurality ofdifferent first hybridization sequences, a mixture of different secondhybridization sequences, and a chemical reaction site. Such “nucleicacid tags” are capable of directing the synthesis of the combinatoriallibrary of the present invention and are also termed“synthesis-directing nucleic acid tags”.

The term “tag-directed synthesis” refers to the fact that the pluralityof compounds synthesized by the methods of the present invention isdirected by the nucleic acid tag.

The term “continuously amplifying population” refers to the continuouslyincreasing plurality of compounds produced by the iterative methods ofthe present invention.

The term “genetic recombination” refers to enrichment of the pluralityof compounds produced by the methods of the present invention for thosecompounds having one or more desired activities by performing the stepsof enrichment, partial digestion, rejoining the partially digestedsequences and further stepwise synthesis to yield a highly enrichedsubpopulation of nucleic acid sequences which are bound to compoundshaving one or more desired activities.

The term “nucleic acid tag(s)” are used interchangably herein below withidentifier oligonucleotide(s) comprising a plurality of nucleic acidtags.

In another aspect, the invention provides combinatorial compoundlibraries which can be subjected to genetic recombination or in vitroevolution by repeated cycles of enrichment and step-wise synthesis,enrichment, PCR amplification and step-wise synthesis or enrichment,partial digestion, reformation and stepwise synthesis to yield a highlyenriched subpopulation of nucleic acids which are bound to compoundshaving one or more desired activities.

The term “selection for a desired activity” means evaluating one or moreof the plurality of compounds produced by the methods of the inventionfor the ability to modulate a chemical or biological reaction.

The term “receptor” refers to a molecule that has an affinity for agiven ligand which can be naturally occurring or synthetic molecule.Receptors can be attached, covalently or noncovalently, to a bindingmember, either directly or via a specific binding substance. Examples ofreceptors include, but are not limited to, antibodies, includingmonoclonal antibodies and antisera reactive with specific antigenicdeterminants (such as on viruses, cells, or other materials), cellmembrane receptors, complex carbohydrates and glycoproteins, enzymes,and hormone receptors.

The term “ligand” refers to a molecule, such as a random peptide orvariable segment sequence, that is recognized by a particular receptor.As one of skill in the art will recognize, a molecule (or macromolecularcomplex) can be both a receptor and a ligand. In general, the bindingpartner having a smaller molecular weight is referred to as the ligandand the binding partner having a greater molecular weight is referred toas a receptor.

The term “modulate” as used herein refers to a change in a particularbiological activity.

Modulation may relate to an increase or a decrease in biologicalactivity, binding characteristics, or any other biological, functional,or immunological property of the molecule.

The term “agonist” as used herein, refers to a molecule which is capableof modulating a biological activity of, e.g., a receptor by inducing,increasing, or prolonging the duration of the biological activitymediated by the receptor. Agonists may themselves be polypeptides,nucleic acids, carbohydrates, lipids, or derivatives thereof, or anyother molecules which bind to and modulate the activity of the receptor.

The term “antagonist” as used herein, refers to a molecule which, whenbound to, e.g., a receptor modulates the activity of the receptor byblocking, decreasing, or shortening the duration of the biologicalactivity mediated by the receptor.

Antagonists may themselves be polypeptides, nucleic acids,carbohydrates, lipids, or derivatives thereof, or any other moleculeswhich bind to and modulate the activity of the receptor.

Other terms used herein should be construed to take on meaningscustomary in the art, unless otherwise defined herein.

Templated Resynthesis of Libraries of Bifunctional Molecules

Methods disclosed herein allows for the synthesis of libraries ofbifunctional molecules and for the subsequent partitioning such asaffinity selection of libraries for the purpose of the identification oflibrary molecules with a desired function.

In some cases it may be beneficial that the identifier tag informationthat is amplified following the partioning step can be used to directthe re-synthesis of the first library for subsequent furtherpartitioning and identification of desired molecules.

Consequently, following an initial split-and-mix synthesis of a libraryof bifunctional molecules according to the present invention and asdisclosed herein and a subsequent partitioning step and optionallyamplification of the identifier tags (identifier oligonucleotides) ofselected molecules, the tags or tag amplification product(s) can be usedas a template for the re-synthesis of the first library or a subset ofthe first library using any process that allows the information of theamplified identifier to direct a templated synthesis of the library.

Following templated synthesis, the generated second library can bepartitioned and the template amplified for identification of desiredmolecules by e.g. sequencing of the isolated identifiers (templates).Alternatively the amplified template can be used to template thesynthesis of a third library being identical to or a subset of the firstor the second library using any process that allows the templatedsynthesis of a library of bifunctional molecules. The process of libraryresynthesis, partitioning and template amplification can be iterated anynumber of times such as 1 time, 2 times, 3 times, 4 times, 5 times, 6times, 7 times, 8 times, 9 times, 10 times or more than 10 times.

Methods that can be used for templated library resynthesis includes butis not limited to (Rasmussen (2006) WO 06/053571A2, Liu et al. (2002),WO 02/074929 A2; Pedersen et al. (2002) WO 02/103008 A2; Pedersen et al.(2003) WO03/078625 A2; Harbury and Halpin, WO 00/23458, Hansen et al WO06/048025. In the method disclosed by Harbury and Halpin, free reactantsare loaded on the reactive site on the identifier in solution orattached to a solid-support. This method of reactant loading in freeform is similar to the methods disclosed herein. Consequently, thebuilding block reactants applied for a first library of bifunctionalmolecules is directly applicable to the templated process described byHalpin and Harbury for second library synthesis. Other methods fortemplated synthesis listed above (Rasmussen (2006) WO 06/053571A2, Liuet al. (2002), WO 02/074929 A2; Pedersen et al. (2002) WO 02/103008 A2;Pedersen et al. (2003) WO03/078625 A2; Hansen et al WO 06/048025 A1,requires the pre-attachment of reactants to oligonucleotides prior tothe chemical reactions required for the templated synthesis of a secondlibrary. Thus, none of the building block reactants applied in a firstlibrary synthesis using the method disclosed herein is directlyapplicable to the synthesis of a second library without priormodification of the reactants and/or appendage to an oligonucleotide.

The following example is included to illustrate the principle oftemplated resynthesis of a library using templates that are amplifiedfrom a pool of identifiers isolated from the screening of a firstlibrary of bifunctional molecules.

Synthesis of a first library is conducted as described elsewhere in theclaims and in example 1 producing a library consisting of app 65.000different bifunctional molecules. The tetramer library consists ofbifunctional molecules each comprising 4 DNA codon elements (tags)covalently linked to the cognate chemical fragments. The overallstructure of the bifunctional molecules is shown in FIG. 51. Each 20nt/bp codon is spaced by a 10 nt fixed region and the tags A-D isflanked by fixed sequences useful for amplification by PCR.

The 65.000 member library was screened against thrombin and the isolatedDNA was amplified as described in example 1 using proof-reading PCR andthe forward and reverse primers 5′-CAAGTCACCAAGAATTCATG and5′-AAGGAACATCATCATGGAT. The PCR product was used as template forlarge-scale 96 wells proof-reading PCR (Pwo Master-mix, Roche) using asimilar primer pair except that the forward primer contained the NH₂-PEGunit described in example 1 and the reverse primer contained a 5′-biotingroup. Following PCR, the content of all wells was pooled, extractedtwice with phenol and once with chloroform before ethanol/acetateprecipitation of the DNA. Following centrifugation the DNA pellet waswashed twice using 70% ethanol, dried and redissolved in 100 ul of 25 mMNH₄-acetate pH 7.25.100 ul SA-beads (Amersham) is washed 3 times with 25mM NH₄-acetate buffer before mixing with the DNA sample and incubationfor 10 min at RT. The sample is washed 3 times with ammonium-acetatebuffer. The non-biotinylated topstrand comprising the 5′ Amino-PEG unitwas eluted by adding 200 ul of H₂O at 90° C. for 30 seconds beforeimmediate spin removal of the SA-beads using a SpinX column (Corning).The singlestranded template is incubated with another 100 ul of SA-beadsand incubated for 10 min at RT before SA-bead removal using SpinXcolumn. The unbound fraction is purified on a microspin 6 column(Bio-rad). This sample containing a singlestranded template withterminal Amino-PEG unit was used for the templated resynthesis of thesecond library essentially according to the method of Halpin andHarbury: DNA Display I. Sequence-Encoded Routing of DNA Populations,PLoS Biol. 2004 July; 2(7): e173. DNA Display II. Genetic Manipulationof Combinatorial Chemistry Libraries for Small-Molecule Evolution, PLoSBiol. 2004 July; 2(7): e174. DNA Display III. Solid-Phase OrganicSynthesis on Unprotected DNA, PloS Biol. 2004 Jul. 2(7): e175.

In brief, the singlestranded template is allocated according to thecodon sequence in position A into specific compartments by hybridizationto a complementary anti-tag immobilised to a solid-support.Consequently, 16 different anti-tags each capable of hybridizingspecifically to one A-codon tag is immobilised on solid-support, placedin individual housings and connected in series. The template is pumpedthrough the compartments in a circular system until the templates areallocated in their cognate compartments. Subsequently, each template istransferred to a DEAE column for chemical reaction with a codon specificbuilding block (reactant) according to Table 1.4A. Following chemicaltransformation and deprotection, all templates are collected from theDEAE column, pooled and redistributed into specific codon B compartmentsin a process similar to that described above for position A.Consequently the allocation, chemical reaction, deprotection, poolingsteps can be iterated for codon positions A to D ultimately producing alibrary a bifunctional molecules using the same building block/codoncombinations as for the initial library enabling the resynthesis of thislibrary based on the identifier/template bias created from thepartitioning of the first library.

Templated Synthesis of a Library of Bifunctional Complexes UsingIdentifier Allocation by Sequential Identifier Subtraction.

Several methods have been disclosed for the templated synthesis of alibrary of bifunctional molecules such as (Rasmussen (2006) WO06/053571A2, Liu et al. (2002), WO 02/074929 A2; Pedersen et al. (2002)WO 02/103008 A2; Pedersen et al. (2003) WO03/078625 A2; Harbury andHalpin, WO 00/23458, Hansen et al WO 06/048025. All methods except forDNA-display (Harbury and Halpin) employ the pre-attachment of reactantsto specific oligonucleotide sequences capable of hybridising to aspecific codon on the template. This pre-attachment is time- andresource consuming and limits the number of commercially availablereactants for library generation. In contrast, the chemicaltransformation using free-form reactants (Halpin and Harbury)dramatically increase building block access, number of chemicalreactions available for library generation and reduce time and resourcesnecessary for preparation of reactants. Consequently, the free-formreactant offers a clear advantage for the fast access to and diversityof chemical transformations. However, the method disclosed by Halpin andHarbury requires specific allocation of the identifier templates intodiscrete compartments. This allocation is conducted by passing the poolof identifier templates through a series of compartments comprisingcompartment specific anti-tags oligonucleotides attached to asolid-support. Such compartment specific allocation is difficult due toproblems with unspecific template allocation resulting in a templatebeing fortuitously trapped in compartments with a non-cognate anti-tag.Ultimately, this results in an illegal reactant/codon combination and areduced fidelity in translation of the template. Furthermore, the singlestranded form of DNA is energetically disfavoured and a complex ssDNAtemplate will tend to take up secondary structure which may result intemplate loss during an allocation step due to lack of hybridisation toa cognate anti-tag. Also, the hybridisation between two complementaryoligonucleotide sequences may be impeded to some extent by the covalentattachment of one oligonucleotide component (anti-tag) to asolid-support compared to a similar duplex formation performed insolution.

The issues above could be resolved by performing the hybridizationbetween a specific anti-tag or a subset pool of anti-tags and thecomplementary identifier sequence(s) in solution. This allows theexperimenter to remove secondary structures in the template f. ex by aheat denaturation step prior to anti-tag hybridization for improvedhybridization kinetics. Subsequently, the anti-tag/identifier duplexesneeds to be retracted from the remaining unbound fraction of identifiersin a first allocation step using a handle supplied on the anti-tag suchas a biotin-group for specific isolation using SA(streptavidin)-beads.Following retraction of the first subset of identifiers the remainingpool of unbound identifiers is denatured before addition of the nextspecific anti-tag or subset of anti-tags and the process of identifiersubset isolation is iterated until all identifiers are allocated ontheir sequence specific subset SA-beads.

Obviously, an iterative process involving fishing out single specificcodon identifier sequences may become unfeasible for large codon sets.Consequently, the entire pool of individual (single) anti-tag sequencescomplementary to the pool of codons at one position such as position Ain the template shown in the figure below, can be subdivided into asubset pool of anti-tags. The subset pools can then be used forsequential subtraction of identifier templates into discrete pools.Following elution of identifiers from each retracted sub-pool thesingle-stranded identifiers are hybridised to a smaller subset ofanti-tags than used for initial round of allocation or using a singleanti-tag from the corresponding first round subset. The sequentialsubtraction can be iterated until each identifier is allocated inseparate compartments according to its unique first codon sequence.

The example below (see FIG. 52) is included to illustrate the use ofsequential subtraction. Initially, 10 subset pools a-j each comprising10 anti-tag totalling 100 anti-tag sequences for codon position A isprepared carrying a purification handle (f. ex a biotin-group).

-   -   i) A singlestranded identifier with a reactive entity is        provided.    -   ii) 1^(st) capture: combine anti-tags complementary to codon        position A in different 10 different pools (a-n) each having 10        anti-tags:    -   (a) 1-10, (b) 11-20, (c) 21-30, (d) 31-40, (e) 41-50, (f)        51-60, (g) 61-70, (h) 71-80, (i) 81-90, (j) 91-100.    -   iii) Add pool a to identifier and hybridize anti-tags to the        cognate subset of identifiers in solution or on solid support.        The bound fraction is subtracted from the pool using the        anti-tag handle.    -   iv) The fraction of unbound identifiers is hybridized to pool b        and subtracted from the identifier pool as above    -   v) Continue the identifier subset subtraction using anti-tag        pool a to j.    -   vi) Elute single-stranded identifier into pool a to j    -   vii) 2^(nd) capture: The subset capture method described above        is used for each subset a to j applying single anti-tags.        Consequently, from pool a, anti-tag 1 is used as a first        hybridizing anti-tag allowing specific subtraction of        identifiers with a codon 1 at position A. The unbound pool of        identifiers is subsequently hybridized with anti-tag 2 for        specific subtraction of identifiers with codon 2 at position A.    -   viii) Repeat identifier subset allocation using all 10 single        anti-tag within specific subgroup allowing specific (single)        allocation of identifiers in 100 subset groups.    -   ix) Chemical reaction using specific reactant/codon combinations        and subsequent deprotection    -   x) Pool identifiers and repeat routing principle for codon        position B

In the example above, two branch allocations are conducted for eachspecific identifier (ie each codon sequence is subset allocated twice).In the first round each identifier is allocated as a subset poolfollowed by a second specific allocation for each unique codon. However,the experimenter may choose any number of branches, any number of subsetpools at each branch and any number of anti-tags in each subset pool.Furthermore, the specific routing conducted for one position iscustom-made for that codon position and, consequently, the experimentercan re-use the branch-profile from one position to any of the remainingpositions or may apply a branch profile that is unique for a codonposition.

Also, the experimenter may use any number of branches such as 1, 2, 3,4, 5, 6, 7, 8, 9, 10 or more than 10 branches in the routing protocol.Furthermore, the experimenter can use any number of subset pools such asany number between 1 and 1.000 or more than 1.000. Also the experimentercan use any number of anti-tags in each subset pool such as any numberbetween 1 and 1.000 or more than 1.000.

The use of multiple branches increase the specificity of the allocationstep, because the level of unspecific allocation is reduced whenconducting more than a single allocation round as described Halpin andHarbury WO 00/23458. In the example below, a principle forsub-allocation of 200 different codons at position for a pool ofidentifier templates is described using 3 branches. In the first branch5 pools of anti-tags each comprising 40 unique anti-tags is used for thesequential subtraction of identifiers into their cognate sub-pools.Following elution of identifiers in each sub-pool, the second branch ofallocation is conducted using a subset of 5 pools of 8 anti-tags each,for the specific retrieval of subsets within their respective 1^(st)branch subset producing a total of 25 sub-pools. Following identifierelution, the 3^(rd) branch of subset allocation is conducted using eachunique anti-tag individually for identifier retrieval subtracted fromtheir cognate subset pool from the 2^(nd) branch resulting in specificsingle allocation of identifiers containing a unique codon at positionA. Subsequently, the identifiers can be eluted e.g. in H2O as describedherein elsewhere and prepared for chemical transformation using acodon-specific reactant, reacted, optionally purified, optionallydeprotected and pooled before re-allocation according to the next codonposition of the identifier template. The process is iterated any numberof times dependent on the number of chemical reactant that need to bereacted and the number of codon positions. Chemical reactions can beconducted by any means compatible with the presence of DNA includingmethods described herein and using methods referred in this document Themethod described here, make use of iterative steps of subtraction ofspecifically formed duplexes between the anti-tags supplied and thecorresponding identifier codon sequences. The method relies on efficientretrieval of the duplexes which can be done using any means useful forisolation of DNA duplexes. Consequently, any entity capable of beinglinked to an anti-tag and useful as handle for purification purposes maybe used for the allocation steps described herein. Specifically, theanti-tags may be supplied with a handle for purification of theduplexex, such as a biotin-group for interaction withstreptavidine-beads or derivatives thereof, a dinitrophenol (DNP) forpurification using DNP-specific antibodies (f.ex covalently attached toa solid-support) or having a chemical entity f.ex a thiol-group capableof reacting forming a covalent link with a solid-support such as2-pyridin-activated thio-sepharose (Amersham Biosciences).

In principle, the anti-tag or pool of anti-tags may be linkedcovalently, or non-covalently to a solid-support prior to hybridizationof the identifier templates.

Templated Resynthesis Step 1: Construction of Anti-Tag Columns

16 different twenty-base capture oligonucleotides were synthesized usingstandard phosphoramidite chemistry, with the addition of aC12-methoxytritylamine modifier at the 5′-end (Glen Research #10-1912,DNA technology, Aarhus Denmark). The HPLC purified oligonucleotides wereloaded on a DEAE column and reacted with Fmoc-amino-PEG24carboxylic-acid (Quanta BioDesign, ltd) using DMT-MM as activatingagent. Excess Fmoc-Amino-PEG linker was removed by collecting theoligonucleotide on a DEAE column followed by Fmoc deprotection by two1-ml treatments with 20% piperidine in DMF, one for 3 min and one for 17min. Following elution from DEAE, the oligonucleotides were purified bymicrospin column gelfiltration (bio-rad) and analysed on ES-MS. Theoligonucleotides were covalently attached to a sepharose resin byincubation with one volume equivalent of drained NHS-activated Sepharose(Amersham Biosciences #17-0906-01). The suspension was rotated at 37° C.ON before addition of 1 M Tris-HCl and incubation ON. The product resinwas washed and could be stored at 4° C. or −20° C.

The derivatized resins were loaded into empty DNA synthesis columnhousings (#CL-1502-1; Biosearch Technologies, Novato, Calif., UnitedStates).

Step 2: ssDNA template hybridization. Approximately 250 ul of DEAESepharose suspension was pipetted into an empty Glen Research columnhousing and washed with 20 ml of H₂O followed by 12 ml of DEAE bindbuffer (10 mM acetic acid and 0.005% Triton X-100) using a syringe or asyringe barrel, a male-male luer adapter, and a vacuum manifold. Thetemplate DNA was loaded onto the washed chemistry column in 1 ml of DEAEbind buffer at approximately 1 ml/min. Anticodon columns were connectedin series to the DEAE column using male tapered luer couplers, capillarytubing, silicone tubing, and tubing connectors. Approximately 3 ml ofhybridization buffer containing 1 nmol of each oligonucleotidecomplementary to the noncoding regions was cyclically pumped over thesystem at 0.5 ml/min for 1 h at 70° C., 10 min at 37° C., and 1 h in a46-° C. water bath within a 37-° C. room. Hybridized DNA was transferredback to fresh individual DEAE columns for loading of the specificreactants,

Step 3: Chemical Reactions at Position A

Chemical reaction on the reactive amino-group on the template wascarried out essentially as described in Halpin and Harbury (PLoS, 2004).To accomplish amino acid additions, columns were washed with 3 ml of DMFand subsequently incubated with 50 mM Fmoc protected-AA shown in table1.4 and 50 mM DMT-MM in 100 ul of coupling mix containing 2% DEA inDIPEA/H2O (95:5) for 10 min. Excess reagent was washed away with 3 mlDMF, and the coupling procedure was repeated. The Fmoc-protecting groupwas then removed by two 1-ml treatments with 20% piperidine in DMF, onefor 3 min and one for 17 min. Finally, the columns were washed with 3 mlof DMF followed by 3 ml of DEAE Bind Buffer (10 mM acetic acid, 0.005%Triton X-100). Identifier templates were eluted with 2 ml of Basic EluteBuffer (1.5 M NaCl, 10 mM NaOH, and 0.005% Triton X-100) heated to 80°C. The DNA was pooled, precipitated with ethanol/acetate, redissolvedand reloaded on a fresh DEAE column.

Subsequent re-allocation according to codon B, C and D. Construction ofanti-tag columns, ssDNA template allocation and transfer to specificDEAE columns for position B, C and D reactions was accomplished usingthe protocol described above for codon A.

Chemical Reaction at Position B

Building block reactants according to Table 1.4B was reacted using 50 mMof reactant, 50 mM DMT-MM in in 100 ul of coupling mix containing 2%DIPEA (N,N′-Diisopropyethylamin) in DMF/H2O (95:5) for 10 min. Excessreagent was washed away with 3 ml DMF, and the coupling procedure wasrepeated. The Msec protection group was removed by addition of 20%piperidine in H2O for 10 min. The process was repeated once.

Chemical Reactions at Position C

Building blocks (reactants) for position C is listed in Table 1.4C

i) Acylation reactions: Conducted as described above.

ii) Isocyanate addition: The DNA on DEAE was washed with 0.5 ml of abuffer containing 100 mM sodium borate and 100 mM sodium phosphate pH8.0 and subsequently incubated with 50 mM of specific isocyanatereactant in CH3CN in the above buffer in a total volume of 100 ul. Thereaction was incubated at 50° C. ON.

iii) Sulphonylation: The DNA on DEAE was washed using 100 mM Na-boratepH 9. Subsequently 10 ul of 100 mM of sulphonylation reactant in THF ismixed with 40 ul of 100 mM Na-borate buffer pH 9 and incubated at 30° C.ON.

Following transformations all resins are washed and the templatedmolecules are Ns deprotected by incubation in a solution of 0.25 Mmercaptoanisol and 0.25 M DIPEA (N,N′-Diisopropylethylamine) in DMF andincubated ON at 25° C. in an eppendorph thermoshaker at 600 rpm. Thenthe material on DEAE was washed with 0.3M AcOH in DMF, then twice withDMF before elution.

Chemical Reactions at Position D

Building blocks (reactants) for position D are listed in Table 1.4DAcylation, isocyanate addition and sulphonylation was carried out asdescribed above.

iv) Nucleophilic aromatic substitution: DNA on DEAE was washed once with0.5 ml 100 mM Na-borate buffer pH 9.0. 25 ul of the reactant in (100 mMin DMSO) was mixed with 25 ul of 100 mM Na-borate pH 9.0 was added andthe reaction incubated at 90° C. ON

v) Reductive amination: DNA on the DEAE resin was washed with 0.5 ml of200 Na-acetate buffer pH 5.0 in 90% DMF followed by incubation of 10 ulof 200 mM reactant in DMSO dissolved in 40 ul of 200 mM Na-acetatebuffer pH 5.0 in 90% DMF and subsequent incubation at 30° C. for 1 hour.Subsequently 25 ul of freshly prepared 140 mM NaCNBH₃ in Na-acetatebuffer pH 5.0 was added followed by incubation ON at 30° C.

Following the final chemical reactions, all samples are subjected to anFmoc deprotection reaction using piperidine as described above (positionA). The DNA is eluted from the DEAE columns, pooled and precipitatedusing ethanol/acetate. Following centrifugation the pellet is washedtwice with 70% ethanol, dried and redissolved in H2O.

Prior to iterating the affinity selections on trombin, thesinglestranded library of bifunctional molecules is converted to adoublestranded form by polymerase extension as described in example 1.

A. An Exemplary Encoding Scheme

The encoding scheme described below represents one of many differentpossible embodiments of the encoding schemes encompassed by the presentinvention in combination with the split-and-mix synthesis methodsdisclosed herein elsewhere. All of the possible encoding schemes thatare encompassed under this invention are based on differentialhybridization to nucleic acid tags during a split-and-recombinesynthesis.

1. The Solid Support.

In the present invention, the conventional solid support (typically apolystyrene/polymethylacrylate bead, or a polyethyleneglycol hybridthereof) has been replaced with a nucleic acid sequence.

In an exemplary embodiment the nucleic acid tag comprises or consists ofat least 220 basepairs and more preferably contains 420 base pairs. Insome cases the nucleic acid tag contains more than 420 base pairs.

In another exemplary embodiment the nucleic acid tag comprises orconsists of from about 40 to 160 basepairs, such as from 60 to 80basepairs, for example from 80 to 100 basepairs, such as from 100 to 120basepairs, for example from 120 to 140 basepairs, such as from 140 to160 basepairs. In some cases the nucleic acid tag contains more than 160basepairs, such as more than 200 base pairs.

In one exemplary embodiment, the nucleic acid tag consists of 21 regionsof twenty base pairs. Eleven of these regions are denoted C,->C″,wherein, C is an abbreviation for “constant” and refers to the “spacer”sequences described above. In this embodiment, the ten remaining regionsare denoted V,->V, o wherein, V is an abbreviation for “variable” andrefers to the hybridization sequences which are different for each groupof subsets of nucleic acid sequences. In this embodiment, every V regionis bordered by two different C regions.

In one exemplary embodiment, the nucleic acid tag consists of 3 regionsof twenty base pairs and 4 regions of ten nucleotides. The 4 regions often nucleotides are denoted C,->C″, wherein, C is an abbreviation for“constant” and refers to the “spacer” sequences described above. In thisembodiment, the 3 regions of twenty nucleotides are denoted V,->V, owherein, V is an abbreviation for “variable” and refers to thehybridization sequences which are different for each group of subsets ofnucleic acid sequences. In this embodiment, every V region is borderedby two different C regions.

In one exemplary embodiment, the nucleic acid tag consists of 4 regionsof twenty base pairs and 5 regions of ten nucleotides. The 5 regions often nucleotides are denoted C,->C″, wherein, C is an abbreviation for“constant” and refers to the “spacer” sequences described above. In thisembodiment, the 4 regions of twenty nucleotides are denoted V,->V, owherein, V is an abbreviation for “variable” and refers to thehybridization sequences which are different for each group of subsets ofnucleic acid sequences. In this embodiment, every V region is borderedby two different C regions.

The pool of nucleic acid tags is degenerate, meaning that almost all ofthe nucleic acid tags differ from one another in nucleotide sequence.The nucleotide differences between different nucleic acid tags resideentirely in the hybridization sequences. For example, in one embodimentin the V, region, ten different twenty base-pair sequences are present.In another embodiment in the V, region, 100 different twenty base-pairsequences are present. Each unique twenty base-pair sequence can bereferred to as a “ZIP code”. Thus ten different “ZIP codes”, denoted a,,b,, c, . . . j,, appear in the V, region of the different nucleic acidtags. Likewise, ten more unique “ZIP codes”, denoted a2, b2, c2 . . .j2, appear in the V2 region of the different nucleic acid tags. A thirdset of 10 or 100 unique ZIP codes appears in the V3 region, etc.

In this embodiment, all of the DNA tags share the same twenty base-pairsequence in designated spacer regions, i.e., the c, spacer region isdenoted z. A different 20 base-pair sequence, z2, appears in the C2region of every DNA tag. Accordingly in an embodiment where the nucleicacid tag contains 420 base pairs, in regions C3->C″, all of the tagshave the spacer sequences Z3->Z, respectively.

Thus each 420 base pair nucleic acid tag consists of an ordered assemblycomposed of 111 different twenty base-pair reactants, the 100 ZIP codes(a″b″c, . . . d5, e5, 5, . . . hlo ilo, jio) and the 11 spacer regions(z, . . . z′). The 111 twenty base-pair reactants have the followingproperties: (i) micromolar concentrations of all 111 sequences hybridizeto their complementary DNA sequences efficiently in solution at aspecified temperature designated Tm, and (ii) the 111 sequences areorthogonal to each other with respect to hybridization, meaning thatnone of the 111 sequences cross-hybridizes efficiently with another ofthe 111 sequences, or with the complement to any of the other 111sequences, at the temperature Tm.

The degenerated identifier oligonucleotides comprising a plurality ofnucleic acid tags can be assembled from their constituent reactants e.g.by the primeness PCR assembly method described by Stemmer et al., Gene164 (1): 49-53 (1995).

However, the identifier oligonucleotides comprising a plurality of tagscan also be provided as described herein above by step-wise ligation oftags. In one embodiment of this method, both tags and anti-tags areligated. In another embodiment, tags are ligated using one or more“splints” capable of hybridising to the tags to be ligated.

2. The Chemical Reaction Site

The 5′alcohol of the 5′base of the nucleic acid tag is modified with acommercially available reagent which introduces a phosphate grouptethered to a linear spacer, e.g., a 12-carbon and terminated with aprimary amine group (e.g., Glen Research catalog#10-1912-xx or numerousother reagents which are available for introducing thiols or otherchemical reaction sites into synthetic DNA).

The primary amine represents the chemical reaction site on which thecompound library is synthesized. Many different types of chemicalreaction sites (in addition to primary amines) can be introduced at the5′terminus of the nucleic acid tag. Exemplary chemical reaction sitesinclude, but are not limited to, chemical components capable of formingamide, ester, urea, urethane, carbon-carbonyl bonds, carbon-nitrogenbonds, carbon-carbon single bonds, olefin bonds, thioether bonds, anddisulfide bonds. In the case of enzymatic synthesis, co-factors can besupplied as are required for effective catalysis. Such co-factors areknown to those of skill in the art. An exemplary cofactor is thephosphopantetheinyl group useful for polyketide synthesis.

B. Carrying Out a DNA-Templated Split

The compound library can be split into subsets at each step of thesplit-and-recombine combinatorial synthesis by differentialhybridization of the nucleic acid tag to complementary oligonucleotidesor oligonucleotide analogs bound to a solid support, e.g., polystyrenebeads.

In a preferred embodiment, the hybridization sequence of each nucleicacid tag comprises at least 10 nucleotides.

The reagents described below are used to carry out the first step of anexemplary encoded split and are analogous to those used to carry outsubsequent splits.

Oligonucleotides or oligonucleotide analogs which represent thecomplementary sequences to each of the hybridization sequences of thenucleic acid tags are synthesized. The 5′ alcohols of the 5′bases of theeach oligonucleotide or oligonucleotide analog are modified with acommercially available reagent which introduces a phosphate grouptethered to a linear spacer, having for example six carbons andterminated with a thiol group (Glen Research catalog#10-1926-xx). Eachof the thiol-bearing oligonucleotides or oligonucleotide analogs isimmobilized through a thioether linkage to a macroporous resin (e.g.,polystyrene, MPS; Biopore catalog#NH-2CM, L-970317) bearingelectrophilic bromoacetamide groups (the preparation of which isdescribed below). Thus a number of affinity resins result, each bearinga unique oligonucleotide or oligonucleotide analog. Each of the affinityresins is loaded into its own column with luerlock fittings at eitherend and the columns connected in a linear sequence.

Numerous variants on the DNA encoding strategy, the attachment ofchemical reaction sites to the DNA, and the specific chemistry orbiochemistry used to construct the compound library are possible.Variation in the specific resins used to carry out the library splits,and to perform the chemical/biochemical coupling steps are alsopossible.

By way of application to the exemplary embodiment described above, thenucleic acid tag comprises 420 base pairs and 10 hybridizationsequences. In this case, 10 different affinity resins and correspondingcolumns are used to form 10 subsets of nucleic acid sequences in eachstep of the synthesis of the compound library.

An exemplary first nucleic acid-encoded split is performed bycontacting, i.e. pumping a high-salt aqueous solution containing theentire pool of different nucleic acid tags cyclically over the linearsequence of affinity columns under high stringency conditions [See,e.g., Southern, E M et al., Nucl Acids Res. 22 (8) 1368-1373 (1994)],using a peristaltic pump for a time sufficient for all of the specifichybridization sequences of each DNA to hybridize to the oligonucleotideor oligonucleotide analogs bound to the columns. The DNA encoded splitis completed simply by breaking the luer-lock linkages between theaffinity columns. At this point the different DNA tags have been dividedinto physically separate subsets on the basis of the specifichybridization sequence in the V region of each tag.

To carry out the DNA-templated split for the second and subsequentsynthetic steps, new affinity columns are prepared which displayoligonucleotides corresponding to additional groups of differenthybridization sequences bound to the polystyrene resin. These columnsseparate the DNA tags into additional subsets on the basis of which ofpossible nucleic acid sequences is present in the hybridization regionof each nucleic acid tag. In a preferred embodiment at least 5 separatehybridization steps are preformed. In an even more preferred embodimentat least 10 separate hybridization steps are preformed.

The MPS resin described above is prepared from commercially availablechloromethyl MPS resin in four steps (Biopore catalog#NH-2CM, L-970317):(i) the chloromethyl MPS resin is coupled to thioglycolic acid (ii) theN-hydroxy succinimide active ester of the coupled thioglycolic acid isprepared (iii) a Jeffamine 1500 molecular weight diamine (Flukechemical#14535) is coupled to the resin by formation of an amide bondwith the thioglycolic active ester (iv) the second amine of the coupledJeffamine is acetylated with bromoacetic anhydride to produce the finalbromoacetamide functionalized MPS resin.

Chemical Coupling

Each subset of nucleic acid tags formed by hybridization as describedabove is subjected to a different synthetic coupling reaction.

By way of example, a polypeptide can be formed by the methods of thepresent invention, as described below.

For synthesis of a polypeptide on the linker substrate in the directionof carboxy to amino terminus, a free amino terminus on the linker isrequired that can be conveniently blocked and deblocked as needed. Apreferred amino terminus blocking group is a fluorenylmethoxycarbonylgroup (FMOC).

For example, to couple an Fmoc-protected amino-acid to the to theprimary amine “chemical reaction site” which is covalently attached tothe synthesis-directing nucleic acid sequence or tag, the followingsteps are carried out: (i) the DNA tags hybridized to the affinitycolumns are transferred onto columns, e.g., hydroxyapatite resin columns(Bio-Rad Macro-Prep Ceramic Hyroxyapatite TYPE II catalog#1588200) withelution in 300 M CaCl or DEAE Sepharose fas (Pharmacia 17-0709-01) withelution in 10 mM acetate at pH 5.0 with 0.005% triton). The DNA tagsremain non-covalently bound to the hydroxyapatite or sepharose resin innumerous organic solvents (for example DMF, acetonitrile, ethanol, andmixtures of those solvents with water). Thus organic reagents can beflowed over the columns and reacted with the chemical reaction sites onthe DNA tags in the same manner that conventional solid phase chemicalsynthesis is carried out. Accordingly, a different Fmoc-protectedamino-acid preactivated with N (1H-benzotriazol-1-yl) (dimethylamino)methylene-N-methylmethanaminium tetrafluoroborate (TBTU) or as anN-hydroxy succimnimide ester in DMF is flowed over each hydroxyapatiteor sepharose column, resulting in the acylation of the primary amines ofthe DNA tags on each of the hydroxyapatite or sepharose columns with anFmoc-protected amino acid [Albericio, F. and Carpino L A, Methods inEnzymology 289: 104-26 (1997)]. Following acylation, the Fmoc group isremoved from the newly added amino acid by flowing a piperidine/DMFsolution over the hydroxyapatite or sepharose columns, thus presenting anew primary amine ready for the next coupling step.

Numerous methods for modification of DNA are known to those of skill inthe art and readily incorporated into the methods described herein [See,e.g., Chu, B C, et al. Nucleic Acids Research 11 (18): 6513-6529(1983)]. By way of further example, nucleotides can be synthesized byvarious methods known to those of skill in the art. [See e.g.,“Oligonucleotide Synthesis: A Practical Approach”, ed. M. J. Gait, JRLPress, New York, N.Y. (1990)].

An entire compound library is synthesized by carrying out alternaterounds of DNAtemplated library splitting and chemical and/or biochemicalcoupling to each subsets of nucleic acid tags.

The plurality of chemical compounds produced by the methods of thepresent invention are linked to nucleic acid sequence tags whichfacilitate identification of the chemical structure.

Conventional DNA sequencing methods are readily available and useful fora determination of the sequence of the synthesis-directing nucleic acidtags. See, e.g., Maniatis et al., eds, MOLECULAR CLONING: A LABORATORYMANUAL, Second Edition, Cold Spring Harbor, N.Y. (1989).

III. Selection, Amplification and Enrichment

The compound library can be screened for a desired activity, for examplethe ability to catalyze a particular reaction or to bind with highaffinity to an immobilized receptor. In most cases, the subpopulation ofmolecules with the desired activity, as well as their nucleic acid tags,are physically partitioned away from siblings during the selection.Following selection, the nucleic acid tags attached to the selectedmolecules are amplified by the polymerase chain reaction [PCR] [Saiki etal, Science 239 (4839) 487-491 (1988)]. The 5′hydroxyl of the 5′-endprimer used to PCR amplify the coding strand is modified with aphosphate group tethered to a fresh primary amine chemical reactionsite. After amplification, the coding strand is separated from thenon-coding strand. Because the nucleic acid tags direct the librarysynthesis in the present invention, rather than merely reporting on thesynthetic history of individual compounds, the coding strands amplifiedfrom the first library can be used to direct the construction of asecond generation compound library. Iteration of this procedure, bycarrying out multiple rounds of selection, DNA tag amplification, andlibrary resynthesis, allows individual desirable compounds to “evolve”from extremely complex libraries.

A. Screening Library for a Desired Activity

An entire compound library or individual library members produced by themethods of the present invention can be evaluated for one or moredesired activities in screening assays capable of distinguishingcompounds which modulate an activity or possess a desired structural orfunctional property.

Exemplary assays and functional analyses include, but are not limitedto, enzymatic assays, non-enzymatic catalytic assays, protein-proteinbinding assays, receptor/ligand binding assays and cell-based assays.More specifically, exemplary cell-based methods provided by the presentinvention are based on; (1) differential binding of library compounds toa cell surface (i.e. binding to cancer cell and not a non-cancer cell),(2) binding of library compounds to components of a cell extract (e.g.,binding to a cell fraction produced by separating an entire cell extracton a sucrose gradient), (3) library compounds capable of endocytosis bya cell, and (4) in vivo localization and binding properties of librarycompounds by injecting the library into an animal. [See, e.g., Arap, W.,et al., Science 279 (5349): 377-80. (1998) which describes in vivoselection of phage display libraries to isolate peptides that homespecifically to tumor blood vessels

As will be appreciated by those of skill in the art, such assays can bepreformed on entire libraries of compounds synthesized by the methodsdescribed herein or sub populations derived therefrom.

The number of possible receptor molecules for which ligands can besynthesized and identified by the methods of the present invention isvirtually unlimited. Exemplary receptor molecules include, but are notlimited to antibodies, growth factors, hormones, enzyme substrates,interferons, interleukins, intracellular and intercellular messengers,lectins, cellular adhesion molecules, and the like. Additional exemplaryligands include, but are not limited to, carbohydrates, non-proteinorganic compounds, metals, peptide mimetics, non-ribosomally producedpolypeptides, conotoxins and polyketides, etc.

Desired compounds produced by the nucleic acid tag-directedcombinatorial library methods of the present invention include, but arenot limited to, small organic molecules, polyketides, subunit oligomersand catalysts for the synthesis of complex molecules from simplesubstrates, e.g., transition metal mediated reactions termed “domino”reactions which are highly efficient processes that allow for productionof large libraries of complex structures in relatively few stepsbeginning with simple precursors. [See, e.g., Tietze and Lieb, Curr OpinChem Biol 2: 63-371 (1998)].

B. In Vitro Evolution of Selected Compounds-Gene Shuffling

In addition to allowing amplification of selected library members, thepresent invention permits evolution of the encoded compound libraries.More specifically, genetic recombination between the nucleic acid tagswhich encode selected subpopulations of compounds is carried out invitro by mutagenesis or random fragmentation of the nucleic acid tagsequence, followed by the generation of related nucleic acid sequences[“gene shuffling”, Stemmer, Nature, 370: 389391 (1994); U.S. Pat. No.5,811,238 (1998)], and subsequent step-wise synthesis of additionalcompounds.

In one embodiment of the invention, a unique restriction site isintroduced into each specific hybridization sequence. By way of example,partial digestion of a library with 11 specific hybridization sequencesis accomplished by partial digestion with 11 corresponding restrictionenzymes, followed by a primeness PCR reassembly reaction, allowing thenucleic acid tags for compounds that have been selected out of thelibrary to be recombined with one another and further synthetic stepscarried out. By analogy to gene shuffling for protein synthesis[Crameri, et al., Nature 391 (6664): 288-291 (1998)], the ability tocarry out genetic recombination of compound libraries vastly increasesthe efficiency with which the diversity in the compound libraries can beexplored and optimized.

Accordingly, the invention provides for polynucleotide shuffling toyield a population of variant nucleic acid sequences, capable ofdirecting the synthesis of structurally-related, and/orfunctionally-related molecules, and/or variants thereof to createcompounds having one or more desired activities. For example, moleculescapable of binding to the 5′untranslated region (UTR) of mRNA can beidentified in this manner.

It is also contemplated that the method of this invention can be usedfor the in vitro amplification of a selected subpopulations of synthesisdirecting nucleic acid tags by PCR, either prior to or following “geneshuffling”.

General Selection Steps and Further Down-Stream Processing Steps

Once a library of bifunctional complexes have been synthesised it ispossible to select and/or screen and/or partition and/or purify thelibrary in order to identify or isolate desirable compounds therefrom.The compounds in one embodiment are small scaffolded molecules.

The partitioning may be based one or more features or properties of amolecule. Such a feature may be associated with or reside in abifunctional molecule or a part of or a combination of parts of theencoded small molecule, the linker, the identifier. Partitioning may bebased a structural, chemical, or electronic feature of a molecule.Partitioning may be based on a feature of a molecule or one or moreparts of the molecule such as affinity for a target, hydrophobicity,hydrophilicity, charge distribution, size, mass, volume, conductivity,electric resistance, reactivity under certain conditions such as bondformation to a target, effect of the molecule such as induction of asignal in a system, e.g. a biochemical system, a biological system suchas cell or a whole organism. The feature may be present in the moleculeor it may be induced by the addition of a cofactor, e.g. a metal ion tothe molecule.

A number of screening methods exist, for the identification ofmolecules, e.g. organic molecules such as the encoded molecule part of abifunctional complex or the tag part of a bifunctional complex, withdesired characteristics. Different types of selection or screeningprotocols are described in (Rasmussen (2006) WO 06/053571A2, Liu et al.(2002), WO 02/074929 A2; Pedersen et al. (2002) WO 02/103008 A2;Pedersen et al. (2003) WO03/078625 A2; Lerner et al., EP 0643778 B1,Encoded combinatorial chemical libraries; Dower et al., EP 0604552 B1;Freskgard et al., WO 2004/039825 A2; Morgan et al., 2005, WO2005/058479; Harbury and Halpin, WO 00/23458). For example, affinityselections may be performed according to the principles used inlibrary-based selection methods such as phage display, polysome display,and mRNA-fusion protein displayed peptides. The template-directedsynthesis of the invention permits selection procedures analogous toother display methods such as phage display (Smith (1985) SCIENCE 228:1315-1317). Phage display selection has been used successfully onpeptides (Wells et al. (1992) CURR. OP. STRUCT. BIOL. 2: 597-604),proteins (Marks et al. (1992) J. BIOL. CHEM. 267: 16007-16010) andantibodies (Winter et al. (1994) ANNU. REV. IMMUNOL. 12: 433-455).Similar selection procedures also are exploited for other types ofdisplay systems such as ribosome display Mattheakis et al. (1994) PROC.NATL. ACAD. Sci. 91: 9022-9026) and mRNA display (Roberts, et al. (1997)PROC. NATL. ACAD. Sci. 94:12297-302).

The invention also relates to a method for identifying a molecule havinga preselected property, comprising the steps of: subjecting the libraryproduced according to the method indicated above to a condition, whereina molecule or a subset of molecules having a predetermined property ispartitioned from the remainder of the library, and identifying themolecule(s) having a preselected function by decoding the identifieroligonucleotide of the complex.

The above method, generally referred to as selection or screening,involves that a library is subjected to a condition in order to selectmolecules having a property which is responsive to this condition. Thecondition may involve the exposure of the library to a target. Thebifunctional complexes having an affinity towards this target can bepartitioned form the remainder of the library by removing non-bindingcomplexes and subsequent eluting under more stringent conditions thecomplexes that have bound to the target. Alternatively, the identifieroligonucleotide of the bifunctional complex can be cleaved from themolecule after the removal of non-binding complexes and the identifieroligonucleotide can be recovered and decoded to identify the molecule.

Specific screening methods employing bifunctional molecules for theidentification of organic molecules with desired characteristics includebut are not limited to:

i. Affinity selection on immobilised target molecules. In this approachthe target molecules (e.g., DNA, RNA, protein, peptide, carbohydrate,organic or inorganic molecule, supramolecular structure or any othermolecule, is immobilized covalently or non-covalently to a solid supportsuch as beads, the bottom of a well of a microtiter plate, a reagenttube, a chromatographic column, or any other type of solid support. Alibrary of bifunctional molecules are now incubated with the immobilizedtarget molecule, excess non-bound bi-functional molecules are washed offby the replacing supernatant or column buffer with buffer not containingbi-functional molecules one or more times. After washing the boundbi-functional molecules are released from solid support by addition ofreagents, specific ligands or the like that results in the elution ofthe bi-functional molecule, or the pH is increased or decreased torelease the bound bi-functional molecules, or the identifier of thebi-functional molecule, e.g., one or both strands of the identifier, isreleased from the encoded molecule with a reagent, pH change orlight-induced cleavage. The recovered identifiers can now optionally beamplified by PCR, optionally cloned and sequenced to reveal thestructure of the ligands encoded by the identifier. As an alternative,the identifiers or bi-functional molecules comprising identifiers, arenot released from solid support, but rather the identifiers areoptionally amplified by PCR and/or analyzed directly while stillimmobilised on solid support. Selection of binding molecules from alibrary can be performed in any format to identify optimal bindingmolecules. Binding selections typically involve immobilizing the desiredtarget molecule, adding a library of potential binders, and removingnon-binders by washing. When the molecules showing low affinity for animmobilized target are washed away, the molecules with a strongeraffinity generally remain attached to the target. The enrichedpopulation remaining bound to the target after stringent washing ispreferably eluted with, for example, acid, chaotropic salts, heat,competitive elution with a known ligand or by proteolytic release of thetarget and/or of template molecules. The eluted templates are suitablefor PCR, leading to many orders of amplification, whereby essentiallyeach selected template becomes available at a greatly increased copynumber for cloning, sequencing, and/or further enrichment ordiversification. In a binding assay, when the concentration of ligand ismuch less than that of the target (as it would be during the selectionof a DNA-templated library), the fraction of ligand bound to target isdetermined by the effective concentration of the target protein. Thefraction of ligand bound to target is a sigmoidal function of theconcentration of target, with the midpoint (50% bound) at [target]=Kd ofthe ligand-target complex. This relationship indicates that thestringency of a specific selection-the minimum ligand affinity requiredto remain bound to the target during the selection-is determined by thetarget concentration. Therefore, selection stringency is controllable byvarying the effective concentration of target. The target molecule(peptide, protein, DNA or other antigen) can be immobilized on a solidsupport, for example, a container wall, a wall of a microtiter platewell. The library preferably is dissolved in aqueous binding buffer inone pot and equilibrated in the presence of immobilized target molecule.Non-binders are washed away with buffer. Those molecules that may bebinding to the target molecule through their attached DNA templatesrather than through their synthetic moieties can be eliminated bywashing the bound library with unfunctionalized templates lacking PCRprimer binding sites. Remaining bound library members then can beeluted, for example, by denaturation. The target molecule can beimmobilized on beads, particularly if there is doubt that the targetmolecule will adsorb sufficiently to a container wall, as may be thecase for an unfolded target eluted from an SDS-PAGE gel. The derivatizedbeads can then be used to separate high-affinity library members fromnonbinders by simply sedimenting the beads in a benchtop centrifuge.Alternatively, the beads clan be used to make an affinity column. Insuch cases, the library is passed through the column, one or more timesto permit binding. The column then is washed to remove nonbindinglibrary members. Magnetic beads are essentially a variant on the above;the target is attached to magnetic beads which are then used in theselection. There are many reactive matrices available for immobilizingthe target molecule, including matrices bearing —NH₂ groups or —SHgroups. The target molecule can be immobilized by conjugation with NHSester or maleimide groups covalently linked to Sepharose beads and theintegrity of known properties of the target molecule can be verified.Activated beads are available with attachment sites for —NH₂ or —COOHgroups (which can be used for coupling). Alternatively, the targetmolecule is blotted onto nitrocellulose or PVDF. When using a blottingstrategy, the blot should be blocked (e.g., with BSA or similar protein)after immobilization of the target to prevent nonspecific binding oflibrary members to the blot.

ii. Affinity selection on target molecules in solution, followed by anymeans of isolation of the bi-functional molecules bound to the target,e.g. by immunoprecipitation of the target-bi-functional moleculecomplexes, capture of the complexes on nitrocellulose filter or byimmobilisation of the target via a functionality on the target such asbiotin or GST-tag or Histidine-tag or other useful means forimmobilization as recognized by a person skilled in the art. A libraryof bi-functional molecules are incubated with target molecules (e.g. aprotein). After complex formation of bi-functional molecules withtarget, the complex is isolated from non-complexes, for example by theaddition of polyvalent antibodies against the target molecule andprecipitation of antibody-target-bi-functional molecule complexes, or isprecipitated by the addition of beads that bind the target molecules.The latter may for example be by addition of streptavidin-coated beadsthat bind to pre-biotinylated targets. The identifiers recovered byprecipitation can now be characterised or amplified, e.g., by PCR, asdescribed in (i). The sequence of the identifiers will reveal theidentity of the encoded molecules that bind the target molecules.

iii. Affinity selection on target molecules in solution, followed by gelretardation, chromatographic separation e.g. size exclusionchromatography, or separation by centrifugation e.g. in aCsCl₂-gradient. A library of bi-functional molecules are incubated withtarget molecules (e.g. a protein). After complex formation ofbi-functional molecules with target, the complex is isolated fromnon-complexes, for example by gel electrophoresis or size exclusionchromatography, or any other chromatographic or non-chromatographicmethod that separates the target-bi-functional molecule complexes fromnon-complexed bi-functional molecules, for example based on thedifference in size and/or charge. The tags of the bi-functionalmolecules of the column fraction or band on the gel that comprisestarget-bi-functional molecule complexes are now characterised oramplified, e.g., by PCR, as described above. The sequence of the tagswill reveal the identity of the encoded molecules that bind the targetmolecules.

iv. Affinity selection on surfaces. Particles, preferably smallparticles, of solid material, e.g., metal particles, metal oxideparticles, grinded plastic, wood, preformed carbon nanotubes, clay,glas, silica, bacterial biofilm or biofilm of other microorganism,cement, solid paint particles, laminate, stone, marble, quartz, textile,paper, skin, hair, cell membranes, industrial membranes, epiderm, or thelike, is added to a solution comprising a library of bi-functionalmolecules. After incubation, one or more washing steps are performed, toremove unbound bi-functional molecules. Then, the bi-functionalmolecules bound to the surface, or the identifiers of the bi-functionalmolecules bound to the surface, are released as described above, and theidentifiers characterised and/or amplified as described above.

v. Selection for intracellularisation. Bi-functional molecules areincubated with cells or micelles, or on one side of a lipid membrane, oron one side of a cell monolayer (e.g. CaCo2 cell monolayer), in order toallow the bi-functional molecule to pass or become immobilized into themembranes. Then, a number of washing steps are performed in order toremove bi-functional molecules that have not become immobilized or havepassed the membrane. Identifiers from bi-functional molecules that havebecome immobilized or have passed the membrane are now amplified and/orcharacterized as described above. The encoded molecule of bi-functionalmolecules that have either become immobilized in the membrane or havepassed the membrane, represent potential transporters forintracellularization, i.e. by attaching these encoded molecules (withoutthe oligonucleotide tag) to e.g. non-oral drugs these may become orallyavailable, because the transporter mediate their transport across thecell.

vi. Selection by phase partitioning. A two- or three phase system may beset up, wherein the bi-functional molecules will partition out according(at least in part) to the characteristics of the encoded molecules.Therefore, the principle allows the identification of encoded moleculesthat have particular preference for a certain kind of solvent. Again,the identifiers of the isolated bi-functional molecules can be amplifiedand/or characterised after the selection has occurred. It may benecessary to coat the nucleic acid component of the bi-functionalmolecule with e.g. DNA binding proteins, in order to ensure that thepartitioning of the bi-functional molecule is significantly correlatedwith the characteristics of the encoded molecule of the bi-functionalmolecule.

vii. Selection for induced dimerisation of target molecules. In apreferred embodiment, encoded molecules are sought that induce thedimerization of target molecules. For example, small molecules with thepotential to induce dimerization of protein receptors in the cellmembrane may be applicable as therapeutics. Thus, a selection protocolfor encoded molecules with the potential to induce dimerization ofproteins A and B is as follows: A library of bi-functional molecules areincubated with proteins A and B. After incubation, the solution isapplied to gel electrophoresis, ultracentrifugation (e.g.CsCl-centrifugation), size exclusion chromatography, or any other kindof separation that separates the protein A-protein B-bi-functionalmolecule-complex from un-complexed protein A and B, and other undesiredcomplexes, such as protein A-protein B-complex. Bi-functional moleculesfrom the band or fraction corresponding to the size and/or charge of theprotein A-protein B-bi-functional molecule-complex is recovered, andtemplate identifiers are then amplified and/or characterised asdescribed above. In this case, the encoded molecule would beresynthesized, and tested in a protein dimerisation assay for its effecton the dimerisation of protein A and B.

viii. Selection by iterative rounds of binding and elution. This is amodification of the methods reported previously (Doyon et al. (2003), J.Am. Chem. Soc., 125, 12372-12373, the content of which is incorporatedherein by reference in its entirety). Bi-functional molecules areincubated with e.g. immobilised target molecule, e.g. a biotinylatedenzyme immobilised on streptavidin beads. After washing one or moretimes, the bound bi-functional molecules are released from solid supportby a change in pH, addition of a detergent such as SDS, or by additionof an excess of ligand that binds the target molecule (the ligand can bee.g. a small molecule, peptide, DNA aptamer or protein that is known tobind the target molecule). Alternatively, the bi-functional moleculesmay be released by degradation of the immobilised target (e.g. bynuclease or protease), denaturation of target by methods such as heat orinduced conformational changes in target structure or the like. Therecovered bi-functional molecules are now re-applied to e.g. immobilisedtarget molecule, optionally after removal or degradation of the ligandor reagent used for elution in the previous step. Again, washing isperformed, and the bound bi-functional molecules eluted. The process ofincubation and binding, washing and elution can be repeated many times,until eventually only bi-functional molecules of high affinity remains.Then the tags of the bi-functional molecules are amplified and/orcharacterised. Using this kind of iterative binding and elution,enrichment factors higher than 1.000.000-fold can be obtained.

Targets may be immobilised on columns, on beads (batch selection), onthe surface of a well, or target and ligands may interact in solution,followed by immunoprecipitation of the target (leading toimmunoprecipitation of ligands bound to target). In one embodiment ofiterative library partioning step(s) the target concentration is keptconstant at all selection steps. In another embodiment it may bedesirable to change the target concentration between or during each orsome partitioning steps. Consequently, the experimenter can choose theaffinity thresholds for molecule recovery based on the moleculesaffinity for the target by altering the target concentration. F. ex afirst selection step may employ a target concentration in the range of1-50 uM (or even higher if practically allowed). Following selection andisolation of the library pool enriched for ligands the library pool isincubated with a target in reduced concentration such as in the range of0.01-5 uM. A reduction in target concentration will enable theexperimenter to increase the recovery of the best ligands in a librarycompared to molecules of lower affinity thereby achieving a better ormore exact ranking of isolated ligands from the library pool based onligand affinity (i.e the number of specific DNA-tags isolated from theselection output correlate directly with molecule affinity for thetarget). In yet another embodiment, the ranking of ligands in aselection output is based on the off-rate of the target-molecule pair.Following the library incubation with immobilised target a specificligand is added which saturate unbound target thus preventing rebindingof library molecules once released from it target binding site. Thisenables the experimenter to isolate library fractions eluted atdifferent timepoints after target saturation resulting in primarily theisolation of molecules according to their off-rates (koff).

It is possible to perform a single or several rounds of selectionagainst a specific target with a subsequently amplification of theselected variants. These obtained variants are then separately tested ina suitable assay. The selection condition can be stringent and specificto obtain binding molecules in one selection rounds. It can beadvantageously to perform the method using a single round of selectionbecause the number and diversity of the potential binders are largercompared to procedures using further selections where potential binderscan be lost. In another embodiment the selection procedure involvesseveral round of selection using increasing stringency conditions.Between each selection an amplification of the selected complex can bedesirable.

x. Whole organism selection. A library of bi-functional molecules,optionally modified by e.g. coating proteins, is injected into a dead orliving animal, for example a mouse. After incubation for a period oftime (e.g two hours) in the animal, specific tissue or organs arerecovered, and the bi-functional molecules associated with specificorgans can be characterised, by e.g. PCR amplification and/or sequencingof the corresponding identifiers. As a specific example, a mousecarrying a tumor can be injected with a library of bi-functionalmolecules. After incubation, the tumor can be isolated from the animal.The bi-functional molecules associated with the tumor are potentialtherapeutics or diagnostics for that cancer.

The abovementioned target molecules may be any supramolecular structure(e.g. nanoclusters, multiprotein complex, ribosomes), macromolecule(e.g. DNA, RNA, protein, polymers such as carbohydrates, thiophenes,fibrin), or low molecular weight compound (e.g. cAMP, small peptidehormones, chelates, morphine, drug). After having performed any of theselections above, the identifiers can taken through one more round ofthe same or another selection protocol. This process can be repeateduntil an appropriately small number of different bi-functional moleculesare recovered.

The selection may be performed in the presence of one or more specificligands for site on a target. For example, if it is desired to avoididentification of ligands to a particular target site, known ligands tothat site may be included during selections. The known ligand may thencompete with bifunctional molecules for binding to the particular sitethus reducing or eliminating binding of bifunctional molecules to thesite. In this way, the bifunctional molecules will not be identifiedbased on their with affinity to the particular target site.

After having performed any of the selections above, the tags of theoutput bi-functional molecules can be amplified by PCR or other means,sequenced and the chemical composition of the molecule identified.

Polyvalent Display and Other Means of Increasing the Likelihood ofIdentifying Encoded Molecules with Weak Characteristics.

Under certain conditions the requirements of an encoded molecule, inorder to be isolated during the screening step, are too strong, and fewor none of the encoded molecules of a library are expected to fulfil therequirements. Such requirements may be for example high affinity or highcatalytic turn-over. The methods and success of multivalent display inaffinity selections is evident from systems similar to that describedhere such as phage display as should be recognized by persons skilled inthe art

Thus, it may be desirable to employ a multivalent display mode, i.e., togenerate libraries of multivalent encoded molecules (multiple encodedmolecules attached to one tag). During a selection step in which forexample an encoded molecule interacts weakly with a target protein, amultivalent encoded molecule may interact with multiple protein targetsthrough the multiple copies of encoded molecules that it contains, andas a result, may bind with higher affinity because of the avidityeffect. Likewise, in a screening or selection step for catalyticefficiency, a multivalent encoded molecule may generate more product ina given time, and may be isolated because of this.

A preferred means of generating libraries of multivalent encodedmolecules each containing multiple copies of the same encoded molecule,is as follows: The DNA tag-piece (denoted “Display oligonucleotide” or“single-stranded identifier”) employed for chemical reaction can besynthesised with 1 or more reactive handles using standardphosphoramidite chemistry. One strategy for the introduction ofmultivalent display involves the incorporation of doublers or treblers(such as Glen Research catalog No 10-1920-90 or 10-1922-90) one or moretimes forming dendrimer structures that can be capped by reactivehandles f.ex amino-, acid-, Thiol- or aldehyde-group (or any chemicalentity useful as starting point in a chemical reaction. This enables theformation of a single DNA sequence connected to any number of reactivehandles such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20 or more reactive handles. FIG. 53 shows 3 examples of asimple quadruple amino-DNA tag enabling synthesis and display of thesame encoded molecule attached to a single encoding tag. It may bedesirable to include spacing groups such as polyethylene glycol (PEG)units at any point in the synthesis process (chosen by the experimenter)for improved synthesis and display of the synthetic molecule.

The multivalent encoded molecules can now be used in various screeningor selection processes. For example, the multivalent encoded moleculesmay be added to an affinity column, to which target protein has beenimmobilised with an appropriately high density, so that multivalentencoded molecules may interact with several immobilised targetssimultaneously. This will lead to the isolation of bi-functionalmolecules that contain encoded molecules with affinity for theimmobilised target protein. The use of multivalent encoded molecules maybe particularly advantageous to use when selecting for affinity to ahomodimeric target molecule, or any other target that contains two ormore identical binding sites. Relevant targets include membrane proteinssuch as the Epo-receptor, p53, HER2, Insulin Receptor, manyinterleukins, palindromic DNA- or RNA-sequences, or fibrin. Divalentencoded molecules containing identical encoded molecules are alsoappropriate for affinity selection on target molecules with one bindingsite, where the binding site is partly or fully symmetrical, andtherefore allows two identical encoded molecules to interact.

In another embodiment the addition of a helper element comprising ahelper molecule known to interact with the target, is linked to anoligonucleotide capable of hybridizing to a region on the DNA portion ofthe bi-functional library molecules may aid the isolation of abifunctional molecule e.g. by increasing the overall affinity of thehelper molecule/bifunctional molecule complex for the target. FIG. 54depicts a scheme for the addition, by hybridization, of a helpermolecule covalently linked to a DNA sequence complementary to the regionof DNA of the bifunctional library molecule that is proximal to thedisplayed molecule. Hybridization of a second primer followed bypolymerase extention and ligation will produce dsDNA displaying both theencoded library molecule and the helper molecule

Consequently, if a ligand is known for a binding site in a protein, thisligand may be coupled to the bi-functional molecule, in order to guidethe encoded molecule to the target protein, and in order to increase theaffinity of the bi-functional molecule (carrying the known ligand) forthe target protein Similar approaches may be used for isolation ofencoded molecules with affinity for a target binding site, where thebinding site can be occupied by both the encoded molecule and the knownligand simultaneously. Finally, it may be desirable to increase theoverall affinity of the bi-functional molecule for the target by linkinga short oligonucleotide that is complementary to the tag of thebi-functional molecule to the target. The short oligonucleotide willthen function as a helper moiety that increases the affinity of thebi-functional molecule for the target, by hybridisation of the shortoligonucleotide to the bi-functional molecule.

Selections employing such bi-functional molecules to which have beenattached a helper moiety may be applied to affinity selection againstall kinds of targets, including protein-heterodimers as well asprotein-homodimers, and thus molecular targets include HER2,Insulin-receptor, VEGF, EGF, IL-4, IL-2, TNF-alpha, the TATA-box ofeukaryotic promoter regions, and many others.

In another embodiment, a target and the bifunctional molecules may bemodified to allow screening. For example, an —SH group may be introducedin a protein target by mutagenesis of an amino acid to a cysteine.Correspondingly, a library of bifunctional molecules may be synthesizedsuch that encoded molecules carry an —SH group. Alternatively, a librarymay following synthesis be reacted with a reactant that carries an —SHgroup. Screenings may then be performed under conditions that induce theformation of an S—S bond between the —SH of the target and the —SH ofthe encoded molecules of the library. In this way, the bifunctionalmolecules may be directed to a specific site on the target.

Dynamic combinatorial library of dimers or trimers of encoded molecules.

The bi-functional molecules of a library may be designed in a way thatleads to transient complex formation between 2, 3, or more bi-functionalcomplexes during the screening process. This may be desirable,especially in cases where the libraries that have been generated arerelatively small, or in cases where it is desirable to screen a largenumber of combinations of encoded molecules for synergistic effects. Inorder to generate transient complexes, the bifunctional molecules may bedesigned so as to comprise half of a transient interaction pair. Forexample, a short single stranded oligonucleotide region may be includedin the design of the tag of the bi-functional molecules; if some of thebifunctional molecules carry a molecular entity “A” and some otherbi-functional molecules of the library carry another molecular entity“B” that interacts transiently, i.e. forms a short-lived complex with,“A”, then the two sets of bi-functional molecules of the library willform transient dimers of bi-functional molecules. These transient dimersmay then be exposed to a screening process, for example affinityselection, where the dimers are then examined for ability to bind to acertain target. As an example, for each of the species of bi-functionalmolecules, half of the generated bi-functional molecules carry the oligosequence 3′-ATGC-5′ in the proximity of the encoded molecule, and theother half of the generated bifunctional molecules carry the oligosequence 3′-GCTA-5′. When all the generated bi-functional molecules areincubated at appropriately low temperature, different combinations ofdimers will transiently form, and allow for a feature displayed by thecombination of the corresponding two encoded molecules to be selectedfor. This feature could be the binding of the two encoded molecules ofthe dimer to bind simultaneously to a target molecule. If appropriatelydesigned, trimers may be (transiently) formed, by formation of triplexDNA between three bi-functional molecules. In this way, all the possibledimers (or trimers) of a pool of bi-functional molecules may be screenedfor the desired feature.

Once the screening of a library of bi-functional molecules has beendone, the isolated bi-functional molecules may be identified. This canbe done without DNA amplification or more preferably by use of PCR orother means of DNA amplification. Next, the structure of the moleculesisolated can be identified from the tag sequence directly usingtechniques such as pyrosequencing described by Margulies, M. et al(Nature. 2005 Sep. 15; 437(7057):376-80) and incorporated herein byreference or by a probing technique described in WO2005093094 or othermeans of direct sequencing without cloning. Alternatively the tags canbe cloned and sequenced by conventional means such as Sanger sequencing,mass spectrometry-based sequencing, single molecule sequencing, orsequencing by hybridisation to oligonucleotide arrays.

The characteristics of the encoded molecules thus identified may now beanalyzed, either in its free form (after resynthesis by organicchemistry or after generation of the bi-functional molecule followed bycleavage of the linker that connects the encoded molecule and itsidentifier) or in its oligonucleotide-linked form (as a bi-functionalmolecule).

QC of Library Generation.

It may be desirable to test reaction efficiencies for the entire set- ora subset of chemical reactions. A simple method for evaluation oftransformations efficiency is the use of Mass spectroscopy for analysisof library transformations. Consequently, a small sample of all reactionwells, a subset or of single wells may be collected and analyseddirectly by any analytical tool available such as MALDI-TOF MS orElectrospray MS. Alternatively the sample may be subjected to a numberof methods for the aid of the analysis. In one embodiment it may bedesirably to purify the identifier from unwanted DNA, chemical entities,buffers etc using methods such as HPLC/FPLC, gelfiltration,Ion-chromatography, Gel-electrophoresis or using immobilisation onsolid-support followed by elution of the library product. Subsequently,the identifier DNA can be analysed using spectroscopic methods includingbut not limited to MALDI-TOF or ES-MS.

In some embodiments it may be necessary to apply additional methods forthe simplification of the analytical step. Since each bifunctionalmolecules generated by the library generation process contains both aDNA part and a chemical part, all samples following the first pool eventcomprises both a heterogeneous DNA part (due to the sequencedifferences) and heterogeneous chemical part due the differences in thechemical composition. Consequently, in order to analyze the chemicalreactions it may be desirable to separate the DNA portion of thebifunctional molecule from the chemical entity. Thus, one method forseparation is the use of a selectively cleavable linker connecting theDNA and the small molecule allowing cleavage and subsequent (optional)removal of the DNA allowing analysis of the remaining chemical fragment.

Selectively cleavable linkers have been described elsewhere and areincorporated herein by reference Pedersen (Pedersen et al. (2002) WO02/103008 A2). One example is the use of a photo-cleavable linkers orthe use of chemically labile linkers such as a linker comprising and S—Sbond which can be selectively cleaved by reducing agents such as DTT orTCEP.

In an alternative approach, a fixed DNA sequence of the DNA-tag thatseparates the chemical entity from the heterologous DNA encoding partmay contain a restriction site recognized by a DNA restrictionendonuclease. Consequently, DNA cleavage would produce a samplecontaining a small uniform DNA segment connected to a heterologouschemical entity. This fragment may be purified by several methods whichinclude but is not restricted to gel-electrophoresis, HPLC orhybridization to a biotinylated DNA-oligonucleotide complementary to theDNA segment comprising the pool of chemical fragments followed bybinding to streptavidine beads (SA-beads) and subsequent elution of theDNA fragments.

The example described below is included to describe one principle forthe evaluation of transformation efficiencies during the generation of alibrary of bifunctional molecules: The example is used to illustrate oneprinciple for quality control on one or more single reactions, a subsetpool of reactions or a sample pool collected from all reactions

In a split and mix library generation procedure n chemical reactions areconducted producing n chemical fragments linked to N different tagsproducing intermediates with a common structure depicted in FIG. 55.

The procedure depicted in FIG. 55 can be conducted at each round ofchemical reaction to monitor reaction efficiencies. If any reactions isnot run satisfactorily, all or only a subset of reactions can beiterated and subject to another round of analysis. Such a process usingchemical reactions followed by QC on the transformation rates can berepeated any number of time until sufficient chemical turn-over isachieved and verified.

For some analysis it may be desirable to purify the sample bygel-electrophoresis or other means such as to harvest the ssDNA or dsDNAidentifier comprising the chemical entity and purify this moiety fromthe remaining DNA in the sample such as unligated surplus tags.Alternatively it may be desirable to purify a singlestranded form of theidentifier f. ex by gel-electrophoresis on UREA-PAGE prior to step 2described above.

Another method for monitoring transformation efficiencies in librarygeneration is to include one or more library mimics, a DNA molecule witha reactive entity, in the library synthesis step(s) containing aspecific DNA sequence preferably unrelated to any sequence used forlibrary tagging. The one or more mimics can be included as tracers tomonitor single-, a subset pool or the entire pool of reactions at anysynthesis or deprotection step during library generation. The mimicswill be chemically transformed similar to the reactive entity on theidentifier in the library generation process and can be included at anyspecific reaction step or at multiple reaction steps. As each mimiccontains a unique DNA sequence, one or more mimics can be specificallysubtracted from the library at any step and analysed for chemicaltransformations. This allows the experimenter to continuously analysethe chemical reaction within the library synthesis by examination of theincluded control mimics. The methods for mimic isolation includes, butis not limited to, purification by UREA-PAGE, HPLC/FPLC or purificationusing binding to a complementary nucleic acids strand, PNA, LNA ormolecule with equivalent specific hybridization function, that carries ahandle, such as a biotin group, useful for purification such as onSA-beads as described above (FIG. 56). Subsequently the mimics can beanalysed by any suitable analytical tool such as MALDI- or ElectrosprayMS.

An alternative method for the purification of the control mimics in thelibrary is to include a selective cleavable linker connecting a handlefor purification and the reactive chemical unit. FIG. 57 depicts thegeneral principle. The reactive unit (site) is any suitable reactivegroups for example but not limited to an amino, thiol, carboxylic-acidor aldehyd-group. The oligonucleotide moiety is optional but provides anexcellent handle for molecular weight analysis using MS. The cleavablelinker (optionally) is selectively cleavable by any means such as e.g.by enzymatic, chemical or photocleavable methods. The purification(optional) may be any unit capable of being selectively recovered.

Templated Synthesis:

In some embodiments it may be desirable to amplify, by PCR or othermeans, the tags recovered from a selection step and use the amplifiedmaterial as template for a subsequent synthesis of a library ofbifunctional molecules. Methods for templated synthesis of bifunctionalmolecules include, but is not restricted to methods disclosed in(Rasmussen (2006) WO 06/053571A2, Liu et al. (2002), WO 02/074929 A2;Pedersen et al. (2002) WO 02/103008 A2; Pedersen et al. (2003)WO03/078625 A2; Harbury and Halpin, WO 00/23458, and further methodsdescribed herein. Alternatively the amplified tags may be used for thepartitioning of a library of bifunctional molecules prior to selectionon a target. This step will enrich a subset of the library byhybridization with the matching tag and the selection procedure(s) canbe iterated with this library subset.

Such pre-selection partitioning of libraries of bifunctional moleculescan be accomplished by various methods which include but is notrestricted to techniques disclosed in Brenner and Lerner (1992, Proc,Natl. Acad. Sci. 89:5381-83 Lerner et al., EP 0643778 B1; EP 0604552 B1;WO2004099441)

The templated library re-synthesis or subset partitioning followed byselection and amplification (optional) step(s) described above may beiterated any number of times. Preferably, the processes are iterateduntil sufficient sequence bias is achieved for easy identification ofligands form tag sequencing.

The characteristics of the encoded molecules thus identified may now beanalyzed, either in its free form (after resynthesis by organicchemistry or after generation of the bi-functional molecule followed bycleavage of the linker that connects the encoded molecule and itsidentifier) or in its oligonucleotide-linked form (as a bi-functionalmolecule).

Once the library has been formed in accordance with the methodsdisclosed herein, one must screen the library for chemical compoundshaving predetermined desirable characteristics. Predetermined desirablecharacteristics can include binding to a target, catalytically changingthe target, chemically reacting with a target in a manner whichalters/modifies the target or the functional activity of the target, andcovalently attaching to the target as in a suicide inhibitor. Inaddition to bioactive species produced as disclosed herein above,bioactive species prepared in accordance with method A and B below, canbe screened according to the present invention.

A. Molecules can be single compounds in their final “state”, which aretagged individually and separately. E.g. single compounds mayindividually be attached to a unique tag. Each unique tag holdsinformation on that specific compound, such as e.g. structure, molecularmass etc.

B. A molecule can be a mixture of compounds, which can be considered tobe in their final “state”. These molecules are normally taggedindividually and separately, i.e. each single compound in a mixture ofcompounds can be attached to the same tag. Another tag can be used foranother mixture of compounds. Each unique tag holds information on thatspecific mixture, such as e.g. spatial position on a plate.

The target can be any compound of interest. The target can be a protein,peptide, carbohydrate, polysaccharide, glycoprotein, hormone, receptor,antigen, antibody, virus, substrate, metabolite, transition stateanalog, cofactor, inhibitor, drug, dye, nutrient, growth factor, cell,tissue, etc. without limitation. Particularly preferred targets include,but are not limited to, angiotensin converting enzyme, renin,cyclooxygenase, 5-lipoxygenase, IIL-10 converting enzyme, cytokinereceptors, PDGF receptor, type II inosine monophosphate dehydrogenase,β-lactamases, and fungal cytochrome P-450. Targets can include, but arenot limited to, bradykinin, neutrophil elastase, the HIV proteins,including tat, rev, gag, int, RT, nucleocapsid etc., VEGF, bFGF, TGFβ,KGF, PDGF, thrombin, theophylline, caffeine, substance P, IgE, sPLA2,red blood cells, glioblastomas, fibrin clots, PBMCs, hCG, lectins,selectins, cytokines, ICP4, complement proteins, etc. The target canalso be for example, a surface (such as metal, plastic, composite,glass, ceramics, rubber, skin, or tissue); a polymer; a catalyst; or atarget biomolecule such as a nucleic acid, a protein (including enzymes,receptors, antibodies, and glycoproteins), a signal molecule (such ascAMP, inositol triphosphate, peptides, or prostaglandins), acarbohydrate, or a lipid. Binding assays can be advantageously combinedwith activity assays for the effect of a reaction product on a functionof a target molecule.

The libraries of the present invention can contain molecules that couldpotentially bind to any known or unknown target. The binding region of atarget molecule could include a catalytic site of an enzyme, a bindingpocket on a receptor (for example, a G-protein coupled receptor), aprotein surface area involved in a protein-protein or protein-nucleicacid interaction (preferably a hot-spot region), or a specific site onDNA (such as the major groove). The natural function of the target couldbe stimulated (agonized), reduced (antagonized), unaffected, orcompletely changed by the binding of the reaction product. This willdepend on the precise binding mode and the particular binding site thereaction product occupies on the target

Functional sites (such as protein-protein interaction or catalyticsites) on proteins often are more prone to bind molecules than are,other more neutral surface areas on a protein. In addition, thesefunctional sites normally contain, a smaller region that seems to beprimarily responsible for the binding energy: the so-called, hot-spotregions (Wells, et al. (1993) RECENT, PROG. HORMONE RES. 48: 253-262).This phenomenon facilitates selection for molecules affecting thebiological function of a certain target

The linkage between the template molecule and reaction product allowsrapid identification of binding molecules using various selectionstrategies. This invention broadly permits identifying binding moleculesfor any known target molecule. In addition, novel unknown targets can bediscovered by isolating binding molecules against unknown antigens(epitopes) and using these binding molecules for identification andvalidation. In another preferred embodiment, the target molecule isdesigned to mimic a transition state of a chemical reaction; one or morereaction products resulting from the selection may stabilize thetransition state and catalyze the chemical reaction.

The upper limit for the strength of the stringency conditions is thedisintegration of the complex comprising the displayed molecule and theencoding region. Screening conditions are known to one of ordinary skillin the art.

Complexes having predetermined desirable characteristics can bepartitioned away from the rest of the library while still attached to anucleic acid identifier tag by various methods known to one of ordinaryskill in the art. In one embodiment of the invention the desirableproducts are partitioned away from the entire library without chemicaldegradation of the attached nucleic acid such that the identifiernucleic acids are amplifiable. The part of the identifier comprising thetags may then be amplified, either still attached to the desirablechemical compound or after separation from the desirable chemicalcompound.

Library members that bind a target molecule can be released bydenaturation, acid, or chaotropic salts. Alternatively, elutionconditions can be more specific to reduce background or to select for adesired specificity. Elution can be accomplished using proteolysis tocleave a linker between the target molecule and the immobilizing surfaceor between the reaction product and the template. Also, elution can beaccomplished by competition with a known competitive ligand for thetarget molecule. Alternatively, a PCR reaction can be performed directlyin the presence of the washed target molecules at the end of theselection procedure. Thus, the binding molecules need not be elutablefrom the target to be selectable since only the template is needed forfurther amplification or cloning, not the reaction product itself.Indeed, some target molecules bind the most avid ligands so tightly thatelution would be difficult.

In a certain embodiment, the desirable molecule acts on the targetwithout any interaction between the coding sequences attached to thedesirable display compound and the target. In one embodiment, thedesirable chemical compounds bind to the target followed by a partitionof the complex from unbound products by a number of methods. The methodsinclude plastic binding, nitrocellulose filter binding, columnchromatography, filtration, affinity chromatography, centrifugation, andother well known methods for immobilizing targets.

Briefly, the library is subjected to the partitioning step, which mayinclude contact between the library and a column onto which the targetis bound. All identifier sequences which do not encode for a reactionproduct having an activity towards the target will pass through thecolumn. Additional undesirable chemical entities (e.g., entities whichcross-react with other targets) can be removed by counter-selectionmethods. Desirable complexes are bound to the column and can be elutedby changing the conditions of the column (e.g., salt, etc.) or theidentifier sequence associated with the desirable chemical compound canbe cleaved off and eluted directly.

In a certain embodiment, the basic steps involve mixing the library ofcomplexes with the immobilized target of interest. The target can beattached to a column matrix or microtitre wells with directimmobilization or by means of antibody binding or other high-affinityinteractions. In another embodiment, the target and displayed moleculesinteract without immobilisation of the target. Displayed molecules thatbind to the target will be retained on this surface, while nonbindingdisplayed molecules will be removed during a single or a series of washsteps. The identifiers of complexes bound to the target can then beseparated by cleaving the physical connection to the synthetic molecule.It can be considered advantageously to perform a chromatography stepafter of (or) instead of the washing step. After the cleavage of thephysical link between the synthetic molecule and the identifier, theidentifier can be recovered from the media and optionally amplifiedbefore the decoding step.

In traditional elution protocols, false positives due to suboptimalbinding and washing conditions are difficult to circumvent and mayrequire elaborate adjustments of experimental conditions. However, anenrichment of more than 100 to 1000 is rarely obtained. The selectionprocess used in example 7 herein alleviates the problem with falsepositive being obtained because the non-specific binding complexes to alarge extent remain in the reaction chamber. The experiments reportedherein suggest that an enrichment of more than 107 can be obtained.

Additionally, chemical compounds which react with a target can beseparated from those products that do not react with the target. In oneexample, a chemical compound which covalently attaches to the target(such as a suicide inhibitor) can be washed under very stringentconditions. The resulting complex can then be treated with proteinase,DNAse or other suitable reagents to cleave a linker and liberate thenucleic acids which are associated with the desirable chemical compound.The liberated nucleic acids can be amplified.

In another example, the predetermined desirable characteristic of thedesirable product is the ability of the product to transfer a chemicalgroup (such as acyl transfer) to the target and thereby inactivate thetarget. One could have a product library where all of the products havea thioester chemical group, or similar activated chemical group. Uponcontact with the target, the desirable products will transfer thechemical group to the target concomitantly changing the desirableproduct from a thioester to a thiol. Therefore, a partitioning methodwhich would identify products that are now thiols (rather thanthioesters) will enable the selection of the desirable products andamplification of the nucleic acid associated therewith.

There are other partitioning and screening processes which arecompatible with this invention that are known to one of ordinary skillin the art. In one embodiment, the products can be fractionated by anumber of common methods and then each fraction is then assayed foractivity. The fractionization methods can include size, pH,hydrophobicity, etc.

To select for a molecule that binds a protein expressible on a cellsurface, such as an ion channel or a transmembrane receptor, the cellsthemselves can be used as the selection agent. The library preferably isfirst exposed to cells not expressing the target molecule on theirsurfaces to remove library members that bind specifically or nonspecifically to other cell surface epitopes. Alternatively, cellslacking the target molecule are present in large excess in the selectionprocess and separable (by fluorescence-activated cell sorting (FACS),for example) from cells bearing the target molecule. In either method,cells bearing the target molecule then are used to isolate librarymembers bearing the target molecule (e.g., by sedimenting the cells or.by FACS sorting). For example, a recombinant DNA encoding the targetmolecule can be introduced into a cell line; library members that bindthe transformed cells but not the untransformed cells are enriched fortarget molecule binders. This approach is also called subtraction,selection and has been used for phage display on antibody libraries(Hoogenboom et al. (1998) IMMUNOTECH 4: 20).

A selection procedure can also involve selection for binding to cellsurface receptors that are internalized so that the. receptor togetherwith the selected binding molecule passes into the cytoplasm, nucleus,or other cellular compartment, such as the Golgi or lysosomes. Dependingon the dissociation rate constant for specific selected bindingmolecules, these molecules may localize primarily within theintracellular compartments. Internalized library members can bedistinguished from molecules attached to the cell surface by washing thecells, preferably with a denaturant. More preferably, standardsubcellular fractionation techniques are used to isolate the selectedlibrary members in a desired subcellular compartment.

An alternative selection protocol also includes a known, weak ligandaffixed to each member of the library. The known ligand guides theselection by interacting with a defined part of the target molecule andfocuses the selection on molecules that bind to the same region,providing a cooperative effect. This can be particularly useful forincreasing the affinity of a ligand with a desired biological functionbut with too low a potency.

Other methods for selection or partitioning are also available for usewith the present invention. These include, for example:immunoprecipitation (direct or indirect) where the target molecule iscaptured together with library members; mobility shift assays in agaroseor polyacrylamide gels, where the selected library members migrate withthe target molecule in a gel; cesium chloride gradient centrifugation toisolate the target molecule with library members; mass spectroscopy toidentify target molecules labeled with library members. In general, anymethod where the library member/target molecule complex can be separatedfrom library members not bound to the target is useful.

The selection process is well suited for optimizations, where theselection steps are made in series, starting with the selection ofbinding molecules and ending with an optimized binding molecule. Theprocedures in each step can be automated using various robotic systems.

Thus, the invention permits supplying a suitable library and targetmolecule to a fully automatic system which finally generates anoptimized binding molecule. Under ideal conditions, this process shouldrun without any requirement for external work outside the robotic systemduring the entire procedure.

The selection methods of the present invention can be combined withsecondary selection or screening identify reaction products capable ofmodifying target molecule function upon binding. Thus, the methods,described herein can be employed to isolate or produce binding moleculesthat bind to and modify the function of any protein or, nucleic acid.

For example, nucleic acid-templated chemistry can be used to identify,isolate, or produce binding molecules (1) affecting catalytic activityof target enzymes by inhibiting catalysis or, modifying substratebinding; (2) affecting the functionality of protein receptors, byinhibiting binding to receptors. or by modifying the specificity ofbinding to receptors; (3) affecting the formation of protein multimersby disrupting the quaternary structure of protein subunits; or (4)modifying transport properties of a protein by disrupting transport ofsmall molecules or ions.

Functional assays can be included in the selection process. For example,after selecting for binding activity, selected library members can bedirectly tested for a desired functional effect, such as an effect oncell signaling. This can, for example, be performed via FACSmethodologies.

The binding molecules of the invention can be selected for otherproperties in addition to binding. For example, to select for stabilityof binding interactions in a desired working environment. If stabilityin the presence of a certain protease is desired, that protease can bepart of the buffer medium used during selection. Similarly, theselection can be performed in serum or cell extracts or in any type ofmedium, aqueous or organic. Conditions that disrupt or degrade thetemplate should however be avoided to allow subsequent amplification.

Selections for other desired properties, such as catalytic or otherfunctional activities, can also be performed. Generally, the selectionshould be designed such that library members with the desired activityare isolatable on that basis from other library members. For example,library members can be screened for the ability to fold or otherwisesignificantly change conformation in the presence of a target molecule,such as a metal ion, or under particular pH or salinity conditions. Thefolded library members can be isolated by performing non-denaturing gelelectrophoresis under the conditions of interest. The folded librarymembers migrate to a different position in the gel and can subsequentlybe extracted from the gel and isolated.

Selection for catalytic activity may be performed by affinity selectionson transition-state analog affinity columns (Baca et al. (1997) PROC.NATL. ACAD. Sci. USA 94 (19): 10063-8) or by function-based selectionschemes (Pedersen et al. (1998) PROC. NATL. ACAD. Sci. USA 95 (18):10523-8).

Similarly, reaction products that fluoresce in the presence of specificligands may be selected by FACS based sorting of translated polymerslinked through their DNA templates to beads. Those beads that fluorescein the presence, but not in the absence, of the target ligand areisolated and, characterized. Useful beads with a homogenous populationof nucleic acid-templates-on any bead can be prepared using, thesplit-ppol synthesis technique on the bead, such that each bead isexposed to only a single nucleotide sequence. Alternatively, a differentasti-“template (each complementary to only a single, different template)can by synthesized on beads using a split-pool” technique, and then cananneal to capture a solution-phase library.

Biotin-terminated biopolymers can be selected for the actual catalysisof bond-. breaking reactions by passing these biopolymers over a resinlinked through a substrate to avidin. Those biopolymers that catalyzesubstrate cleavage self-elute from a column charged with this resin.Similarly, biotin-terminated biopolymers can be selected for thecatalysis of bond-forming reactions. One substrate is linked to resinand the second substrate is linked to avidin. Biopolymers that catalyzebond formation between the substrates are selected by their ability toreact the substrates together, resulting in attachment of the biopolymerto the resin.

Library members can also be selected for their catalytic effects onsynthesis of a polymer to which the template is or becomes attached. Forexample, the library member may influence the selection of monomer unitsto be polymerized as well as how the polymerization reaction takes place(e.g., stereochemistry, tacticity, activity). The synthesized polymerscan be selected for specific properties, such as, molecular weight,density, hydrophobicity, tacticity, stereoselectivity, using standardtechniques, such as, electrophoresis, gel filtration, centrifugalsedimentation, or partitioning into solvents of differenthydrophobicities. The attached template that directed the synthesis ofthe polymer can then be identified.

Library members that catalyze virtually any reaction causing bondformation between two substrate molecules or resulting in bond breakageinto two product molecules can be selected. To select for bond formingcatalysts (for example, hetero Diels-Alder, Heck coupling, aldolreaction, or olefin metathesis catalysts), library members arecovalently linked to one substrate through their 5′. amino or thioltermini. The other substrate of the reaction is synthesized as aderivative linked to biotin. When dilute solutions of library-substrateconjugate are combined with the substrate-biotin conjugate, thoselibrary members that catalyze bond formation cause the biotin group tobecome covalently attached to themselves. Active bond forming catalystscan then be separated from inactive library members by capturing theformer with immobilized streptavidin and washing away inactive librarymembers. In an analogous manner, library members that catalyze bondcleavage reactions such as retro-aldol reactions, amide hydrolysis,elimination reactions, or olefin dihydroxylation followed by periodatecleavage can be selected. In this case, library members are covalentlylinked to biotinylated substrates such that the bond breakage reactioncauses the disconnection of the biotin moiety from the library members.Upon incubation under reaction conditions, active catalysts, but notinactive library members, induce the loss of their biotin groups.Streptavidin-linked beads can then be used to capture inactive polymers,while active catalysts are able to be eluted from the beads. Relatedbond formation and bond cleavage selections have been used successfullyin catalytic RNA and DNA evolution (Jaschke et al. (2000) CURR. OPIN.CHEM. BIOL. 4: 257-62) Although these selections do not explicitlyselect for multiple turnover catalysis, RNAs and DNAs selected in thismanner have in general proven to be multiple turnover catalysts whenseparated from their substrate moieties (Jaschke et al. (2000) CURR.OPIN. CHEM. BIOL. 4: 257-62; Jaeger et al. (1999) PROC. NATL. ACAD. Sci.USA 96: 14712-7; Bartel et al. (1993) SCIENCE 261:1411-8; Sen et al.(1998) CURR. OPIN. CHEM. BIOL. 2:680-7).

In addition to simply evolving active catalysts, the in vitro selectionsdescribed above are used to evolve non-natural polymer libraries inpowerful directions difficult to achieve using other catalyst discoveryapproaches. Substrate specificity among catalysts can be selected byselecting for active catalysts in the presence of the desired substrateand then selecting for inactive catalysts in the presence of one or moreundesired substrates. If the desired and undesired substrates differ bytheir configuration at one or more stereocenters, enantioselective ordiastereoselective catalysts can emerge from rounds of selection.Similarly, metal selectivity can be evolved by selecting for activecatalysts in the presence of desired metals and selecting for inactivecatalysts in the presence of undesired metals. Conversely, catalystswith broad substrate tolerance can be evolved by varying substratestructures between successive rounds of iteration.

Alternatively, following PCR amplification of DNA templates encodingselected synthetic molecules, additional rounds of translation,selection, and amplification can be conducted to enrich the library forhigh affinity binders. The stringency of the selection is graduallyincreased by increasing the salt concentration of the binding andwashing buffers, decreasing the duration of binding, elevating thebinding and washing temperatures, and increasing the concentration ofwashing additives such as template DNA or unrelated proteins.

Importantly, in vitro selections can also select for specificity inaddition to binding affinity. Library screening methods for bindingspecificity typically require duplicating the entire screen for eachtarget or non-target of interest. In contrast, selections forspecificity can be performed in a single experiment by selecting fortarget binding as well as for the inability to bind one or morenon-targets. Thus, the library can be pre-depleted by removing librarymembers that bind to a non-target. Alternatively, or in addition,selection for binding to the target molecule can be performed in thepresence of an excess of one or more non-targets. To maximizespecificity, the non-target can be a homologous molecule. If the targetmolecule is a protein, appropriate non-target proteins include, forexample, a generally promiscuous protein such as an albumin. If thebinding assay is designed to target only a specific portion of a targetmolecule, the non-target can be a variation on the molecule in whichthat portion has been changed or removed.

Ultimately, a binding molecule identified using the present inventionmay be useful as a therapeutic and/or diagnostic agent. Once theselection is complete, the selected templates optionally can beamplified and sequenced. The selected reaction products, if present insufficient quantity, can be separated from the templates, purified(e.g., by HPLC, column chromatography, or other chromatographic method),and further characterized.

Inherent in the present method is the selection of chemical entities onthe basis of a desired function; this can be extended to the selectionof small molecules with a desired function and specificity. Specificitycan be required during the selection process by first extractingidentifiers sequences of chemical compounds which are capable ofinteracting with a non-desired “target” (negative selection, orcounter-selection), followed by positive selection with the desiredtarget. As an example, inhibitors of fungal cytochrome P-450 are knownto cross-react to some extent with mammalian cytochrome P-450 (resultingin serious side effects). Highly specific inhibitors of the fungalcytochrome could be selected from a library by first removing thoseproducts capable of interacting with the mammalian cytochrome, followedby retention of the remaining products which are capable of interactingwith the fungal cytochrome.

Amplification of Identifier Oligonucleotides

PCR amplification methods are described in detail in U.S. Pat. Nos.4,683,192, 4,683,202, 4,800,159, and 4,965,188, and at least in PCRTechnology: Principles and Applications for DNA Amplification, H.Erlich, ed., Stockton Press, New York (1989); and PCR Protocols: A Guideto Methods and Applications, Innis et al., eds., Academic Press, SanDiego, Calif. (1990). The contents of all the foregoing documents areincorporated herein by reference.

The identifier oligonucleotide can be amplified using PCR with primersgenerating two unique cut-sites. These cut-sites can be used formultimerization of the coding region by cloning into a suitable vectorfor sequencing. This approach will allow simultaneously sequencing ofmany encoding regions. Alternatively, the PCR product is directly clonedinto a suitable vector using for example TA cloning. In still anotherapproach the identity of the molecule is established by applying the PCRproduct to a suitable microarray.

It is preferred that the oligonucleotide parts of the bifunctionalcomplexes of the libraries of the invention have a common terminalsequence which can serve as a primer for PCR, as is known in the art.Such a common terminal sequence can be incorporated as the terminal endof a tag added in the final cycle of the library synthesis, or it can beadded following library synthesis, for example, using the enzymaticligation methods disclosed herein.

In embodiments in which PCR is to be used to amplify the identifieroligonucleotides of selected bifunctional complexes, the identifieroligonucleotides preferably include PCR primer sequences. For example, aPCR primer sequence can be included in the display oligonucleotideand/or it can be included with the first tag oligonucleotide. Theidentifier oligonucleotide can also include a capping PCR primersequence that follows the tag sequences. The capping sequence can beligated to the identifier oligonucleotide following the final cycle oflibrary synthesis or it can be included in the tag oligonucleotide ofthe final cycle. In cases in which the PCR primer sequences are includedin a tag oligonucleotide, these tag oligonucleotides will be longer thanthe tag oligonucleotides added in the other cycles, because they willinclude both a tag sequence and a PCR primer sequence.

In cases in which the capping sequence is added after the addition ofthe final reactant and the final tag oligonucleotide, the synthesis of alibrary as set forth herein will include the step of ligating thecapping sequence to the identifier oligonucleotide, such that theoligonucleotide portion of substantially all of the library membersterminates in a sequence that includes a PCR primer sequence.

PCR primer sequences suitable for use in the libraries of the inventionare known in the art; suitable primers and methods are set forth, forexample, in Innis et al., eds., PCR Protocols: A Guide to Methods andApplications, San Diego: Academic Press (1990), the contents of whichare incorporated herein by reference in their entirety. Preferably, thecapping sequence is added by ligation to the pooled fractions which areproducts of the final synthesis round. The capping sequence can be addedusing the enzymatic process used in the construction of the library.

As indicated above, the nucleotide sequence of the oligonucleotide tagas part of the methods of this invention, may be determined by the useof the polymerase chain reaction (PCR).

The nucleic acid sequence of an oligonucleotide tag can be determined bysubjecting the oligonucleotide tag to a PCR reaction as follows. Theappropriate sample is contacted with a PCR primer pair, each member ofthe pair having a preselected nucleotide sequence. The PCR primer pairis capable of initiating primer extension reactions by hybridizing to aPCR primer binding site on the identifier oligonucleotide tag. The PCRprimer binding site is preferably designed into the identifieroligonucleotide tag. For example, a PCR primer binding site may beincorporated into the initial (display) oligonucleotide tag and thesecond PCR primer binding site may be in the final oligonucleotide tag.Alternatively, the second PCR primer binding site may be incorporatedinto the capping sequence as described herein. In preferred embodiments,the PCR primer binding site is at least about 5, 7, 10, 13, 15, 17, 20,22, or 25 nucleotides in length.

The PCR reaction can be performed by mixing the PCR primer pair,preferably a predetermined amount thereof, with the identifieroligonucleotide, preferably a predetermined amount thereof, in a PCRbuffer to form a PCR reaction admixture. The admixture is thermocycledfor a number of cycles, which is typically predetermined, sufficient forthe formation of a PCR reaction product. A sufficient amount of productis one that can be isolated in a sufficient amount to allow for DNAsequence determination.

PCR is typically carried out by thermocycling i.e. repeatedly increasingand decreasing the temperature of a PCR reaction admixture within atemperature range whose lower limit is about 30 C to about 55 C andwhose upper limit is about 90 C to about 100 C. The increasing anddecreasing steps can be continuous, but is preferably phasic with timeperiods of relative temperature stability at each of temperaturesfavoring polynucleotide synthesis, denaturation and hybridization.

The PCR reaction can be performed using any suitable method. Generallyit occurs in a buffered aqueous solution, i.e. a PCR buffer, preferablyat a pH of 7-9. Preferably, a molar excess of the primer is present. Alarge molar excess is preferred to improve the efficiency of theprocess.

The PCR buffer also contains the deoxyribonucleotide triphosphates(polynucleotide synthesis substrates) dATP, dCTP, dGTP and dTTP and apolymerase, typically thermostable, all in adequate amounts for primerextension (polynucleotide synthesis) reaction. The resulting solution(PCR mixture) is-heated to about 90 C-100 C for about 1 to 10 minutes,preferably from 1 to 4 minutes. After this heating period the solutionis allowed to cool to 54 C, which is preferable for primerhybridization.

The synthesis reaction may occur at a temperature ranging from roomtemperature up to a temperature above which the polymerase no longerfunctions efficiently. Suitable enzymes for elongating the primersequences include, for example, E. coli DNA polymerase I, Taq DNApolymerase, Klenow fragment of E. coli DNA polymerase I, T4 DNApolymerase, other available DNA polymerases, reverse transcriptase, andother enzymes, including heat-stable enzymes, which will facilitatecombination of the nucleotides in the proper manner to form the primerextension products which are complementary to each nucleic acid strand.Generally, the synthesis will be initiated at the 3′ end of each primerand proceed in the 5′direction along the template strand, untilsynthesis terminates, producing molecules of different lengths. Thenewly synthesized DNA strand and its complementary strand form adouble-stranded molecule which can be used in the succeeding steps ofthe analysis process.

Ultra High-Throughput Methods

Tags and/or identifiers may be analyzed by an ultra high throughputmethod, such as ultra high throughput sequencing as described hereinbelow. Often following a screen or affinity assay using encodedmolecules e.g. phage display, DNA display, mRNA display, or other typesof tagged compounds, the results of screening may be analyzed bysampling a limited number of tags, e.g. 1-100 tags. Tags may be analyzedby cloning individual tags e.g. by cloning in E. coli followed bypreparation of plasmids or “colony PCR” and then sequencing using anymethod known in the art. However, it is often desirable to analyse asignificantly larger number of tags to obtain more information from thescreening which makes these traditional methods of cloning andsequencing cumbersome. For example, a single type of sequencecorresponding to a specific combination of codons may dominate a smalltag sample e.g. 40 of 100 tags may correspond to a single codoncombination and the remaining tags may be different. If instead 1000 or10000 tags are analysed it is expected that about 400 and 4000 sequencesrespectively correspond to the tag observed 40 of 100 times in the smallsample. However the remaining 600 and 6000 sequences respectively mayreveal several sequences that are observed more than once thusindicating that they have been preferentially enriched during thescreening. Thus a potential wealth of information exists which is verycumbersome to access using traditional methods, e.g. e.g. by cloning inE. coli followed by preparation of plasmids or “colony PCR” and thensequencing. Several methods can be applied to analyze tags in an ultrahigh-throughput fashion. For example identifiers may be analyzed by anultra high-throughput method similar to that described in patent WO0120039 and Margulies M et al (Genome sequencing in microfabricatedhigh-density picolitre reactors, Nature 2005). This method involvescapture of individual PCR-derived fragments on their own beads and,within the droplets of an emulsion, clonally amplifying the individualfragment. Unlike in current sequencing technology, this approach doesnot require subcloning in bacteria or the handling of individual clones;the templates are handled in bulk within the emulsions. Sequencing canbe done by synthesis simultaneously in open wells of a fibre-optic slideusing a modified pyrosequencing protocol that is designed to takeadvantage of the small scale of the wells. The fibreoptic slides aremanufactured by slicing of a fibre-optic block that is obtained byrepeated drawing and fusing of optic fibres. At each iteration, thediameters of the individual fibres decrease as they are hexagonallypacked into bundles of increasing cross-sectional sizes. Eachfibre-optic core is 44 μm in diameter and surrounded by 2-3 μm ofcladding; etching of each core creates reaction wells approximately 55μm in depth with a centre-to-centre distance of 50 μm, resulting in acalculated well size of 75 pl (picoliters). The slide, containingapproximately 1.6 million wells, is loaded with beads and mounted in aflow chamber designed to create a 300-mm high channel, above the wellopenings, through which the sequencing reagents flow The unetched baseof the slide is in optical contact with a second fibre optic imagingbundle bonded to a charge-coupled device (CCD) sensor, allowing thecapture of emitted photons from the bottom of each individual well. Thecombination of picolitre-sized wells, enzyme loading uniformity allowedby the small beads and enhanced solid support chemistry enables a methodthat extends the useful read length of sequencing-by-synthesis to morethan 100 bases.

Identifiers may also be analyzed by an ultra high-throughput methodsimilar to that described in WO/2005/093094. This method relates to“high-density fingerprinting”, in which a panel of nucleic acid probesis annealed to nucleic acid information is desired, e.g. an identifier,with determination of the presence or absence of sequence complementaryto a panel of probes, thus providing sequence information. The methodinvolves hybridization of a panel of probes, each probe comprising oneor more oligonucleotide molecules, in sequential steps determining foreach probe if it hybridizes to the template or not, thus forming the“hybridization fingerprint” of the target. Preferably, the panel ofprobes and the length of the template strand are adjusted to ensuredense coverage of any given template strand with indicative probes'(probes which hybridize exactly once to the template strand). Probes maybe 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or nucleotides long. Probes maycontain any natural or unnatural nucleotide or analog. The obtainedhybridization spectrum can then be compared with a reference databasecontaining all expected identifier sequences. Before probing,identifiers or derived products may be immobilized in an array format.Then identifiers may be amplified e.g. using rolling-circleamplification or a related method. Thus individual identifier sequencesare placed apart and amplified avoiding the need for traditionalcumbersome cloning e.g. in e. coli.

Identifiers may also be analyzed by an ultra high-throughput methodsimilar to that described in WO/2001/057248. By this method identifiersor amplified or modified identifiers may be immobilized in an arrayformat. Primers may be annealed to the identifiers and the sequence ofthe identifiers may be determined by sequencing. Seqeuncing in an arrayformat can be done by various methods recognized by those skilled in theart. For example, incorporation of fluorescently-labeled, 3′-blockednucleotides can be done in the presence of a DNA polymerase. Nucleotidemay be any natural or unnatural nucleotide or any nucleotide analog. Thepolymerase incorporates a base complementary to the targetpolynucleotide, but is prevented from further addition by the3′-blocking group. The label of the incorporated base can then bedetermined and the blocking group removed by chemical cleavage to allowfurther polymerisation to occur. The fluorescent group can also beremoved thus allowing detection of a new nucleotide incorporation at aspecific array position. Prior to immobilization, a hairpin adaptor maybe ligated to the identifier sequence such that a primer becomescovalently linked to the identifier.

The information carried by tags may be analyzed using a computerapplication, e.g. a word or text processing application, a spreadsheetapplication. Preferably, the tag information may be analyzed using acomputer application which can translate the tag information into e.g.encoded structures. A computer application may preferably be used toanalyze such encoded structures include quantitative and qualitativestructure-activity relationship (SAR) analyses e.g. such as analyzingand/or clustering structural fingerprints common to enriched encodedstructures. A simple but efficient method is to look for tagcombinations which have been enriched by the screening process.

It may be found that only specific reactants or dimers formed byreactants, e.g., dimers formed by the first and the second reactant orthe first and the third reactant are enriched by a screening process.Such a result may indicate that the screening process has not beenoptimized and steps can be taken to improve the screening process. If alarge number of molecules with e.g. same or very similar target affinityexist in a library of bifunctional complexes it may be difficult orimpossible to optimize the screening process so that it can discriminatesufficiently between them. The tag analysis may then identify a commonreactant combination shared by the tags whereas one reactant positionmay be “undefined” i.e. it is not possible to determine which reactantis preferred at this position, e.g. the “C” position in the followinglist of tag combinations, where identifiers are composed of three tags(A-B-C): A2-B17-C13, A1-B1-C2, A1-B1-C14, A1-B1-C23, A1-B1-C17,A5-B278-C11. In this case is preferable to obtain significantly more tagsequences as this may enable discrimination of different but similarreactant combinations. This can be achieved by using ultrahigh-throughput tag sequencing methods as described.

Following screening or analyses of identifiers the pool of identifiersmay be subjected to further methods which may aid analyses of theidentifiers. Such methods may include partitioning the identifiers basedon specific features of the identifiers such as a nucleotide sequence.For example a subset of identifiers may contain too many variants of atag combination or it may contains too much noise, e.g. identifierswhich are deemed uninteresting. In such cases nested PCR may be used toamplify only identifiers which contain specific tags. The resultingamplification product may then be processed e.g. sequencing, optionallyin an ultra high-throughput fashion, to identify a common tag at anotherwise unresolved position. Alternatively, tag combinations may beenriched by partitioning single-stranded identifier oligonucleotidese.g. sequentially with anticodons corresponding to specific tagsessentially performing an affinity selection/screening of theidentifiers with or without encoded molecules. In this way it ispossible to partition specific identifiers or identifier subsets.

Targets

The methods described herein may involve partitioning of molecules orbifunctional complexes according to their affinity for a target. Targetsmay be protein or non-protein as discussed elsewhere. In the case ofprotein targets a list of applicable targets may be obtained e.g. byaccessing an public database such as a NCBI database(http://www.ncbi.nlm.nih.gov/entrez/guery.fcgi?db=Protein). In the caseof human enzymes and receptors, targets may be retrieved from saiddatabase using e.g. “Human” and “Enzyme” or “Receptor” as querykeywords. Moreover, a list of targets can be retrieved from the “Mode ofAction” section of the Medtrack database (medtrack.com).

A target suitable for use with the methods described herein can beselected from the list consisting of:

1:) (2′-5′)oligo(A) synthetase (EC 2.7.7.-), splice form 8-2—human; (2:)[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase,mitochondrial precursor (Branched-chain alpha-keto acid dehydrogenasekinase) (BCKDHKIN) (BCKD-kinase); (3:) [Protein ADP-ribosylarginine]hydrolase (ADP-ribosylargininehydrolase) (ADP-ribose-L-arginine cleavingenzyme); (4:) 1,4-alpha-glucan branching enzyme; (5:) 11beta-hydroxysteroid dehydrogenase type II; (6:) 11-beta-hydroxysteroiddehydrogenase 1 [Homo sapiens]; (7:) 130 kDa leucine-rich protein (LRP130) (GP130) (Leucine-rich PPR motif-containing protein); (8:) 130 kDaphosphatidylinositol 4,5-biphosphate-dependent ARF1 GTPase-activatingprotein (PIP2-dependent ARF1 GAP) (ADP-ribosylation factor-directedGTPase-activating protein 1) (ARFGTPase-activating protein 1)(Development and differentiation-enhancing factor 1); (9:) 14-3-3protein zeta/delta (Protein kinase C inhibitor protein 1) (KCIP-1);(10:) 15-hydroxyprostaglandin dehydrogenase [NAD+] (PGDH)(Prostaglandindehydrogenase 1); (11:) 17 beta hydroxysteroiddehydrogenase type 2; (12:) 17beta-hydroxysteroid dehydrogenase type10/short chain L-3-hydroxyacyl-CoA dehydrogenase [Homo sapiens]; (13:)17beta-hydroxysteroid dehydrogenase type 7 form 2 [Homo sapiens]; (14:)1-acylglycerol-3-phosphate O-acyltransferase 1 [Homo sapiens]; (15:)1-acylglycerol-3-phosphate O-acyltransferase 5 [Homo sapiens]; (16:)1-aminocyclopropane-1-carboxylate synthase [Homo sapiens]; (17:)1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma2(Phosphoinositide phospholipase C) (PLC-gamma-2) (PhospholipaseC-gamma-2) (PLC-IV); (18:) 2,4-dienoyl CoA reductase 1 precursor [Homosapiens]; (19:) 2,4-dienoyl-CoA reductase, mitochondrial precursor(2,4-dienoyl-CoA reductase [NADPH]) (4-enoyl-CoA reductase [NADPH]);(20:) 2′,5′-oligoadenylate synthetase 1 isoform 1 [Homo sapiens]; (21:)2′,5′-oligoadenylate synthetase 1 isoform 2 [Homo sapiens]; (22:)2′,5′-oligoadenylate synthetase 1 isoform 3 [Homo sapiens]; (23:)2-5A-dependent ribonuclease (2-5A-dependent RNase) (Ribonuclease L)(RNase L) (Ribonuclease 4); (24:) 25-hydroxyvitamin D-1 alphahydroxylase, mitochondrial precursor (Cytochrome P450 subfamily XXVIIBpolypeptide 1) (Cytochrome p45027B1) (Calcidiol 1-monooxygenase)(25-OHD-1 alpha-hydroxylase) (25-hydroxyvitamin D(3)1-alpha-hydroxylase) (VD31A hydroxylase) (P450C1 alpha) (P450VD1-alpha);(25:) 25-hydroxyvitamin D-1-alpha-hydroxylase [Homo sapiens]; (26:)2′-5′oligoadenylate synthetase 3 [Homo sapiens]; (27:)2′-5′-oligoadenylate synthetase-like isoform a [Homo sapiens]; (28:)2′-5′-oligoadenylate synthetase-like isoform b [Homo sapiens]; (29:) 26Sproteasome non-ATPase regulatory subunit 2 (26S proteasome regulatorysubunit RPN1) (26S proteasome regulatory subunit S2) (26S proteasomesubunit p97) (Tumor necrosis factor type 1 receptor-associated protein2) (55.11 protein); (30:) 26S proteasome non-ATPase regulatory subunit 7(26S proteasome regulatory subunit rpn8) (26S proteasome regulatorysubunit S12) (Proteasome subunit p40) (Mov34 protein homolog); (31:)2-acylglycerol O-acyltransferase 2 (MonoacylglycerolO-acyltransferase 2)(Acyl CoA:monoacylglycerol acyltransferase 2) (MGAT2) (hMGAT2)(Diacylglycerol acyltransferase 2-like protein 5) (DiacylglycerolO-acyltransferase candidate 5) (hDC5); (32:) 2-acylglycerolO-acyltransferase 3 (MonoacylglycerolO-acyltransferase 3) (AcylCoA:monoacylglycerol acyltransferase 3) (MGAT3) (Diacylglycerolacyltransferase 2-like protein 7) (Diacylglycerol O-acyltransferasecandidate 7) (hDC7); (33:) 2-amino-3-carboxymuconate-6-semialdehydedecarboxylase; (34:) 2-amino-3-ketobutyrate coenzyme A ligase,mitochondrial precursor (AKB ligase) (Glycine acetyltransferase); (35:)2-amino-3-ketobutyrate-CoA ligase [Homo sapiens]; (36:) 2-aminoadipic6-semialdehyde dehydrogenase [Homo sapiens]; (37:) 2-enoyl-CoAhydratase, 3-hydroxyacyl-CoA dehydrogenase, 3-oxoacyl-CoA thiolase, TFEbeta=trifunctional enzyme beta subunit {N-terminal} [human, liver,Peptide Mitochondrial Partial, 16 aa]; (38:) 2-hydroxyacyl-CoA lyase 1[Homo sapiens]; (39:) 2-hydroxyacylsphingosine1-beta-galactosyltransferase (EC 2.4.1.45)—human; (40:)2-hydroxyphytanoyl-CoA lyase (2-HPCL); (41:) 2-hydroxyphytanoyl-CoAlyase [Homo sapiens]; (42:) 2-oxoglutarate dehydrogenase E1 component,mitochondrial precursor (Alpha-ketoglutarate dehydrogenase); (43:)2-oxoglutarate receptor 1 (Alpha-ketoglutarate receptor 1) (G-proteincoupled receptor 80) (G-protein coupled receptor 99) (P2Y purinoceptor15) (P2Y-like nucleotide receptor) (P2Y-like GPCR); (44:) “3beta-hydroxysteroid dehydrogenase/delta 5-->4-isomerase type1(3Beta-HSD 1) (Trophoblast antigen FDO161G) [Includes:3-beta-hydroxy-delta(5)-steroid dehydrogenase(3-beta-hydroxy-5-enesteroid dehydrogenase) (Progesterone reductase);Steroid delta-isomerase (Delta-5-3-ketosteroid isomerase)].”; (45:) “3beta-hydroxysteroid dehydrogenase/delta 5-->4-isomerase type II(3Beta-HSD II) [Includes:) 3-beta-hydroxy-delta(5)-steroid dehydrogenase(3-beta-hydroxy-5-ene steroid dehydrogenase) (Progesterone reductase);Steroid delta-isomerase(Delta-5-3-ketosteroid isomerase)].”; (46:) 3′histone mRNA exonuclease 1 (3′-5′ exonuclease ERI1) (Eri-1 homolog)(Histone mRNA 3′ end-specific exoribonuclease) (Protein3′hExo) (HEXO);(47:) 3′(2′),5′-bisphosphate nucleotidase 1 (Bisphosphate3′-nucleotidase 1) (PAP-inositol-1,4-phosphatase) (PIP); (48:)3,2-trans-enoyl-CoA isomerase, mitochondrial precursor (Dodecenoyl-CoAisomerase) (Delta(3),delta(2)-enoyl-CoA isomerase) (D3,D2-enoyl-CoAisomerase); (49:) 3′,5′-cyclic nucleotide phosphodiesterase (EC3.1.4.17) 8B1-human; (50:) 3-hydroxy-3-methylglutaryl coenzyme Areductase; (51:) “3-hydroxyacyl-CoA dehydrogenase; peroxisomal enoyl-CoAhydratase[Homo sapiens].”; (52:) 3-hydroxybutyrate dehydrogenaseprecursor [Homo sapiens]; (53:) 3-hydroxybutyrate dehydrogenase type 2(R-beta-hydroxybutyrate dehydrogenase) (Dehydrogenase/reductase SDRfamily member 6) (Oxidoreductase UCPA); (54:) 3-hydroxybutyratedehydrogenase, type 2 [Homo sapiens]; (55:) 3-hydroxyisobutyratedehydrogenase [Homo sapiens]; (56:)3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase(hydroxymethylglutaricaciduria) [Homo sapiens]; (57:) 3-keto-steroidreductase (Estradiol 17-beta-dehydrogenase 7) (17-beta-HSD 7)(17-beta-hydroxysteroid dehydrogenase 7); (58:) 3-mercaptopyruvatesulfurtransferase [Homo sapiens]; (59:) 3-methylcrotonyl-CoA carboxylasealpha subunit [Homo sapiens]; (60:) 3-methylcrotonyl-CoA carboxylasebiotin-containing subunit [Homo sapiens]; (61:) 3-oxo-5 alpha-steroid4-dehydrogenase 2 [Homo sapiens]; (62:) 3-oxo-5-beta-steroid4-dehydrogenase (Delta(4)-3-ketosteroid 5-beta-reductase) (Aldo-ketoreductase family 1 member D1); (63:) 3-oxoacid CoA transferase 1precursor [Homo sapiens]; (64:) 3-oxoacyl-[acyl-carrier-protein]synthase, mitochondrial precursor (Beta-ketoacyl synthase); (65:)3′-phosphoadenosine 5′-phosphosulfate synthase 1 [Homo sapiens]; (66:)3′phosphoadenosine 5′-phosphosulfate synthase 2b isoform [Homo sapiens];(67:) 40 kDa peptidyl-prolyl cis-trans isomerase (PPIase) (Rotamase)(Cyclophilin-40) (CYP-40) (Cyclophilin-related protein); (68:)4a-carbinolamine dehydratase; (69:) 4-alpha-glucanotransferase (EC2.4.1.25)/amylo-1,6-glucosidase (EC 3.2.1.33)-human; (70:)4-aminobutyrate aminotransferase precursor [Homo sapiens]; (71:)4-trimethylaminobutyraldehyde dehydrogenase (TMABADH)(Aldehydedehydrogenase 9A1) (Aldehyde dehydrogenase E3 isozyme)(Gamma-aminobutyraldehyde dehydrogenase)(R-aminobutyraldehydedehydrogenase); (72:) 5′ nucleotidase, ecto [Homosapiens]; (73:) 5′(3′)-deoxyribonucleotidase, cytosolic type (Cytosolic5′,3′-pyrimidine nucleotidase) (Deoxy-5′-nucleotidase 1) (dNT-1); (74:)5,10-methylenetetrahydrofolate reductase (NADPH) [Homo sapiens]; (75:)5′,3′-nucleotidase, cytosolic [Homo sapiens]; (76:) 5′,3′-nucleotidase,mitochondrial precursor [Homo sapiens]; (77:) 52 kD Ro/SSA autoantigen[Homo sapiens]; (78:) 5-aminoimidazole-4-carboxamide ribonucleotideformyltransferase/IMP cyclohydrolase [Homo sapiens]; (79:)5-aminolevulinate synthase, erythroid-specific, mitochondrial precursor(5-aminolevulinic acid synthase) (Delta-aminolevulinate synthase)(Delta-ALA synthetase) (ALAS-E); (80:) 5-aminolevulinate synthase,nonspecific, mitochondrial precursor (5-aminolevulinic acid synthase)(Delta-aminolevulinate synthase) (Delta-ALA synthetase) (ALAS-H); (81:)5-beta steroid reductase [Homo sapiens]; (82:) 5-hydroxytryptamine 1Areceptor (5-HT-1A) (Serotonin receptor 1A) (5-HT1A) (G-21); (83:)5-hydroxytryptamine 1B receptor (5-HT-1B) (Serotonin receptor 1B)(5-HT1B) (5-HT-1D-beta) (Serotonin 1D beta receptor) (S12); (84:)5-hydroxytryptamine 1D receptor (5-HT-1D) (Serotonin receptor 1D)(5-HT-1D-alpha); (85:) 5-hydroxytryptamine 1E receptor (5-HT-1E)(Serotonin receptor 1E) (5-HT1E) (S31); (86:) 5-hydroxytryptamine 1Freceptor (5-HT-1F) (Serotonin receptor 1F); (87:) 5-hydroxytryptamine 2Areceptor (5-HT-2A) (Serotonin receptor 2A) (5-HT-2); (88:)5-hydroxytryptamine 2B receptor (5-HT-2B) (Serotonin receptor 2B); (89:)5-hydroxytryptamine 2C receptor (5-HT-2C) (Serotonin receptor 2C)(5-HT2C) (5-HTR2C) (5HT-1C); (90:) 5-hydroxytryptamine 3 receptorprecursor (5-HT-3) (Serotonin-gated ion channel receptor) (5-HT3R);(91:) 5-hydroxytryptamine 4 receptor (5-HT-4) (Serotonin receptor 4)(5-HT4); (92:) 5-hydroxytryptamine 5A receptor (5-HT-5A) (Serotoninreceptor 5A) (5-HT-5); (93:) 5-hydroxytryptamine 6 receptor (5-HT-6)(Serotonin receptor 6); (94:) 5-hydroxytryptamine 7 receptor (5-HT-7)(Serotonin receptor 7) (5-HT-X) (5HT7); (95:)5-methyltetrahydrofolate-homocysteine methyltransferase [Homo sapiens];(96:) 5′-methylthioadenosine phosphorylase [Homo sapiens]; (97:)5′-nucleotidase, cytosolic II [Homo sapiens]; (98:) 5′-nucleotidase,cytosolic III isoform 1 [Homo sapiens]; (99:) 6-phosphofructo-2-kinase(EC 2.7.1.105)/fructose-2,6-bisphosphate 2-phosphatase (EC3.1.3.46)—human; (100:)“6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1(6PF-2-K/Fru-2,6-P2ASE liver isozyme) [Includes: 6-phosphofructo-2-kinase;Fructose-2,6-bisphosphatase].”; (101:)6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 isoform a[Homosapiens]; (102:) 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2isoform b[Homo sapiens]; (103:)“6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2(6PF-2-K/Fru-2,6-P2ASE heart-type isozyme) (PFK-2/FBPase-2) [Includes:)6-phosphofructo-2-kinase; Fructose-2,6-bisphosphatase].”; (104:)6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 [Homo sapiens];(105:) 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 spliceisoform 3 [Homo sapiens]; (106:)6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 splice isoform 4[Homo sapiens]; (107:)6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 splice isoform 5[Homo sapiens]; (108:)“6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4(6PF-2-K/Fru-2,6-P2ASE testis-type isozyme) [Includes:6-phosphofructo-2-kinase; Fructose-2,6-bisphosphatase].”; (109:)6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 isoform 2-[Homosapiens]; (110:) 6-phosphofructokinase (EC 2.7.1.11), hepatic—human;(111:) 6-phosphofructokinase type C (Phosphofructokinase 1)(Phosphohexokinase) (Phosphofructo-1-kinase isozyme C) (PFK-C)(6-phosphofructokinase, platelet type); (112:) 6-phosphofructokinase,liver type (Phosphofructokinase 1) (Phosphohexokinase)(Phosphofructo-1-kinase isozyme B) (PFK-B); (113:)6-phosphofructokinase, muscle type (Phosphofructokinase 1)(Phosphohexokinase) (Phosphofructo-1-kinase isozyme A) (PFK-A)(Phosphofructokinase-M); (114:) 6-phosphogluconolactonase (6PGL); (115:)6-pyruvoyl tetrahydrobiopterin synthase (PTPS) (PTP synthase); (116:)6-pyruvoyltetrahydropterin synthase [Homo sapiens]; (117:)7,8-dihydro-8-oxoguanine triphosphatase (8-oxo-dGTPase)(Nucleosidediphosphate-linked moiety X motif 1) (Nudix motif 1); (118:)72 kDa type IV collagenase precursor (72 kDa gelatinase)(Matrixmetalloproteinase-2) (MMP-2) (Gelatinase A) (TBE-1); (119:) 85kDa calcium-independent phospholipase A2 (iPLA2) (Cal-PLA2) (Group VIphospholipase A2) (GVI PLA2); (120:) 8-hydroxyguanine-DNA glycosylase[Homo sapiens]; (121:) 8-oxo-7,8-dihydroguanosine triphophatase—human;(122:) 8-oxo-dGTPase [Homo sapiens]; (123:) 8-oxoguanine DNA glycosylase1 [Homo sapiens]; (124:) 8-oxoguanine DNA glycosylase homolog 1 [Homosapiens]; (125:) 8-oxoguanine DNA glycosylase isoform 1a [Homo sapiens];(126:) 8-oxoguanine DNA glycosylase isoform 1b [Homo sapiens]; (127:)8-oxoguanine DNA glycosylase isoform 1c [Homo sapiens]; (128:)8-oxoguanine DNA glycosylase isoform 2a [Homo sapiens]; (129:)8-oxoguanine DNA glycosylase isoform 2b [Homo sapiens]; (130:)8-oxoguanine DNA glycosylase isoform 2c [Homo sapiens]; (131:)8-oxoguanine DNA glycosylase isoform 2d [Homo sapiens]; (132:)8-oxoguanine DNA glycosylase isoform 2e [Homo sapiens]; (133:) 92-kDatype IV collagenase [Homo sapiens]; (134:) 9-cis-retinol specificdehydrogenase [Homo sapiens]; (135:) A Transferase [Homo sapiens];(136:) A/G-specific adenine DNA glycosylase (MutY homolog) (hMYH);(137:) ACAD 10 [Homo sapiens]; (138:) Ac-CoA carboxylase; (139:) ACE2[Homo sapiens]; (140:) ACE-related carboxypeptidase ACE2 [Homo sapiens];(141:) Acetoacetyl-CoA synthetase [Homo sapiens]; (142:) Acetolactatesynthase [Homo sapiens]; (143:) acetolactate synthase homolog; (144:)Acetylcholine receptor protein subunit alpha precursor; (145:)Acetylcholine receptor protein subunit beta precursor; (146:)Acetylcholine receptor protein subunit delta precursor; (147:)Acetylcholine receptor protein subunit epsilon precursor; (148:)Acetylcholine receptor protein subunit gamma precursor; (149:)Acetylcholinesterase collagenic tail peptide precursor (AChE Q subunit)(Acetylcholinesterase-associated collagen); (150:) acetylcholinesterasecollagen-like tail subunit [Homo sapiens]; (151:) acetylcholinesterasecollagen-like tail subunit isoform I precursor [Homo sapiens]; (152:)acetylcholinesterase collagen-like tail subunit isoform II [Homosapiens]; (153:) acetylcholinesterase collagen-like tail subunit isoformIII [Homo sapiens]; (154:) acetylcholinesterase collagen-like tailsubunit isoform III precursor [Homo sapiens]; (155:)acetylcholinesterase collagen-like tail subunit isoform IV [Homosapiens]; (156:) acetylcholinesterase collagen-like tail subunit isoformIV precursor [Homo sapiens]; (157:) acetylcholinesterase collagen-liketail subunit isoform V [Homo sapiens]; (158:) acetylcholinesterasecollagen-like tail subunit isoform V precursor [Homo sapiens]; (159:)acetylcholinesterase collagen-like tail subunit isoform VI [Homosapiens]; (160:) acetylcholinesterase collagen-like tail subunit isoformVII [Homo sapiens]; (161:) acetylcholinesterase collagen-like tailsubunit isoform VIII [Homo sapiens]; (162:) acetylcholinesterasecollagen-like tail subunit isoform VIII precursor [Homo sapiens]; (163:)acetylcholinesterase collagen-like tail subunit isoform VII precursor[Homo sapiens]; (164:) acetylcholinesterase collagen-like tail subunitisoform VI precursor [Homo sapiens]; (165:) acetylcholinesterase isoformE4-E5 precursor [Homo sapiens]; (166:) acetyl-CoA carboxylase (EC6.4.1.2)—human; (167:) Acetyl-CoA carboxylase 1 (ACC-alpha) [Includes:)Biotin carboxylase]; (168:) acetyl-CoA carboxylase 1 [Homo sapiens];(169:) Acetyl-CoA carboxylase 2 (ACC-beta) [Includes:) Biotincarboxylase]; (170:) acetyl-CoA carboxylase 2 [Homo sapiens]; (171:)Acetyl-CoA carboxylase 2 variant [Homo sapiens]; (172:) acetyl-CoAcarboxylase alpha [Homo sapiens]; (173:) acetyl-CoA synthetase [Homosapiens]; (174:) acetyl-Coenzyme A acetyltransferase 1 precursor [Homosapiens]; (175:) acetyl-Coenzyme A acetyltransferase 2 [Homo sapiens];(176:) acetyl-Coenzyme A acyltransferase 1 [Homo sapiens]; (177:)acetyl-Coenzyme A carboxylase alpha isoform 1 [Homo sapiens]; (178:)acetyl-Coenzyme A carboxylase alpha isoform 2 [Homo sapiens]; (179:)acetyl-Coenzyme A carboxylase alpha isoform 3 [Homo sapiens]; (180:)acetyl-Coenzyme A carboxylase alpha isoform 4 [Homo sapiens]; (181:)acetyl-Coenzyme A carboxylase beta [Homo sapiens]; (182:)Acetyl-coenzyme A synthetase 2-like, mitochondrial precursor(Acetate-CoA ligase 2) (Acetyl-CoA synthetase 2) (Acyl-CoA synthetaseshort-chain family member 1); (183:) Acetyl-coenzyme A synthetase,cytoplasmic (Acetate-CoA ligase) (Acyl-activating enzyme) (Acetyl-CoAsynthetase) (ACS) (AceCS) (Acyl-CoA synthetase short-chain family member2); (184:) acid alpha-glucosidase preproprotein [Homo sapiens]; (185:)acid phosphatase 1 isoform b [Homo sapiens]; (186:) acid phosphatase 1isoform c [Homo sapiens]; (187:) acid phosphatase 1 isoform d [Homosapiens]; (188:) acid phosphatase 6, lysophosphatidic [Homo sapiens];(189:) acid phosphatase; (190:) aconitase 2 precursor [Homo sapiens];(191:) Aconitate hydratase, mitochondrial precursor (Citratehydro-lyase) (Aconitase); (192:) acrosin precursor [Homo sapiens];(193:) ACSBG2 protein [Homo sapiens]; (194:) ACSL1 protein [Homosapiens]; (195:) ACSL3 protein [Homo sapiens]; (196:) ACSL6 protein[Homo sapiens]; (197:) ACSM1 protein [Homo sapiens]; (198:) ACSS2protein [Homo sapiens]; (199:) activating transcription factor 2 [Homosapiens]; (200:) activation of Sentrin/SUMO protein AOS1 [Homo sapiens];(201:) activation-induced cytidine deaminase [Homo sapiens]; (202:)activin A receptor, type IC [Homo sapiens]; (203:) activin A receptor,type IIA precursor [Homo sapiens]; (204:) activin A type IB receptorisoform a precursor [Homo sapiens]; (205:) activin A type IB receptorisoform b precursor [Homo sapiens]; (206:) activin A type IB receptorisoform c precursor [Homo sapiens]; (207:) activin A type IIB receptorprecursor [Homo sapiens]; (208:) Activin receptor type IB precursor(ACTR-IB) (Serine/threonine-protein kinase receptor R2) (SKR2) (Activinreceptor-like kinase 4) (ALK-4); (209:) Activin receptor type 1Cprecursor (ACTR-IC) (Activin receptor-like kinase 7) (ALK-7); (210:)Activin receptor type 2A precursor (Activin receptor type IIA)(ACTR-IIA) (ACTRIIA); (211:) Activin receptor type 2B precursor (Activinreceptor type IIB) (ACTR-IIB); (212:) Activin receptor type-1 precursor(Activin receptor type I) (ACTR-I) (Serine/threonine-protein kinasereceptor R1) (SKR1) (Activin receptor-like kinase 2) (ALK-2) (TGF-Bsuperfamily receptor type 1) (TSR-I); (213:) acyl coenzyme A:cholesterolacyltransferase [Homo sapiens]; (214:) acyl coenzyme A:monoacylglycerolacyltransferase 3 [Homo sapiens]; (215:) acylamino acid-releasing enzyme[Homo sapiens]; (216:) Acylamino-acid-releasing enzyme (AARE)(Acyl-peptide hydrolase) (APH) (Acylaminoacyl-peptidase) (Oxidizedprotein hydrolase) (OPH) (DNF15S2 protein); (217:) Acyl-CoAdehydrogenase family member 8, mitochondrial precursor (ACAD-8)(Isobutyryl-CoA dehydrogenase) (Activator-recruited cofactor 42 kDacomponent) (ARC42); (218:) Acyl-CoA synthetase 3 [Homo sapiens]; (219:)acyl-CoA synthetase 4 [Homo sapiens]; (220:) Acyl-CoA synthetasebubblegum family member 2 [Homo sapiens]; (221:) acyl-CoA synthetaselong-chain family member 1 [Homo sapiens]; (222:) acyl-CoA synthetaselong-chain family member 1 isoform a [Homo sapiens]; (223:) acyl-CoAsynthetase long-chain family member 1 isoform c [Homo sapiens]; (224:)acyl-CoA synthetase long-chain family member 3 [Homo sapiens]; (225:)Acyl-CoA synthetase long-chain family member 4 [Homo sapiens]; (226:)acyl-CoA synthetase long-chain family member 4 isoform 1 [Homo sapiens];(227:) acyl-CoA synthetase long-chain family member 4 isoform 2 [Homosapiens]; (228:) Acyl-CoA synthetase long-chain family member 5 [Homosapiens]; (229:) acyl-CoA synthetase long-chain family member 5 isoforma [Homo sapiens]; (230:) acyl-CoA synthetase long-chain family member 5isoform b [Homo sapiens]; (231:) acyl-CoA synthetase long-chain familymember 6 isoform a [Homo sapiens]; (232:) acyl-CoA synthetase long-chainfamily member 6 isoform b [Homo sapiens]; (233:) acyl-CoA synthetaselong-chain family member 6 isoform d [Homo sapiens]; (234:) acyl-CoAsynthetase long-chain family member 6 isoform e [Homo sapiens]; (235:)Acyl-CoA synthetase medium-chain family member 3 [Homo sapiens]; (236:)Acyl-CoA synthetase short-chain family member 1 [Homo sapiens]; (237:)Acyl-CoA synthetase short-chain family member 2 [Homo sapiens]; (238:)acyl-CoA synthetase short-chain family member 2 isoform 1 [Homosapiens]; (239:) acyl-CoA synthetase short-chain family member 2 isoform2 [Homo sapiens]; (240:) acyl-CoA synthetase-like protein [Homosapiens]; (241:) Acyl-CoA wax alcohol acyltransferase 1(Long-chain-alcoholO-fatty-acyltransferase 1) (DiacylglycerolO-acyltransferase 2-like protein 3) (Diacyl-glycerol acyltransferase 2);(242:) Acyl-CoA wax alcohol acyltransferase 2(Long-chain-alcoholO-fatty-acyltransferase 2) (Wax synthase) (hWS)(MultifunctionalO-acyltransferase) (Diacylglycerol O-acyltransferase2-like protein4) (Diacylglycerol O-acyltransferase candidate 4) (hDC4);(243:) acyl-Coenzyme A dehydrogenase family, member 10 [Homo sapiens];(244:) Acyl-Coenzyme A dehydrogenase family, member 11 [Homo sapiens];(245:) acyl-Coenzyme A dehydrogenase family, member 8 [Homo sapiens];(246:) acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chainprecursor[Homo sapiens]; (247:) acyl-Coenzyme A dehydrogenase, C-4 toC-12 straight chain [Homo sapiens]; (248:) acyl-Coenzyme Adehydrogenase, long chain precursor [Homo sapiens]; (249:) acyl-CoenzymeA dehydrogenase, short/branched chain precursor [Homo sapiens]; (250:)acyl-Coenzyme A oxidase 2, branched chain [Homo sapiens]; (251:)acyl-Coenzyme A oxidase 3, pristanoyl [Homo sapiens]; (252:)acyl-Coenzyme A oxidase isoform a [Homo sapiens]; (253:) acyl-Coenzyme Aoxidase isoform b [Homo sapiens]; (254:) Acyl-coenzyme A thioesterase 8(Acyl-CoA thioesterase 8) (Peroxisomal acyl-coenzyme A thioesterhydrolase 1) (PTE-1) (Peroxisomal long-chain acyl-coA thioesterase 1)(HIV-Nef-associated acyl coA thioesterase) (Thioesterase II) (hTE)(hACTEIII) (hACTE-III) (PTE-2); (255:) acyl-malonyl condensing enzyme[Homo sapiens]; (256:) acyl-malonyl condensing enzyme 1 [Homo sapiens];(257:) acyloxyacyl hydrolase precursor [Homo sapiens]; (258:)acyloxyacyl hydrolase; (259:) ADAM 10 precursor (A disintegrin andmetalloproteinase domain 10) (Mammalian disintegrin-metalloprotease)(Kuzbanian protein homolog) (CDw156c antigen); (260:) ADAM 17 precursor(A disintegrin and metalloproteinase domain 17) (TNF-alpha-convertingenzyme) (TNF-alpha convertase) (Snake venom-like protease) (CD156bantigen); (261:) ADAM metallopeptidase domain 10 [Homo sapiens]; (262:)ADAM metallopeptidase domain 12 isoform 1 preproprotein [Homo sapiens];(263:) ADAM metallopeptidase domain 12 isoform 2 preproprotein [Homosapiens]; (264:) ADAM metallopeptidase domain 17 preproprotein [Homosapiens]; (265:) ADAM metallopeptidase domain 19 isoform 1 preproprotein[Homo sapiens]; (266:) ADAM metallopeptidase domain 19 isoform 2preproprotein [Homo sapiens]; (267:) ADAM metallopeptidase domain 33isoform alpha preproprotein [Homo sapiens]; (268:) ADAM metallopeptidasedomain 33 isoform beta preproprotein [Homo sapiens]; (269:) ADAMmetallopeptidase with thrombospondin type 1 motif, 12preproprotein [Homosapiens]; (270:) ADAM metallopeptidase with thrombospondin type 1 motif,13 isoform1 preproprotein [Homo sapiens]; (271:) ADAM metallopeptidasewith thrombospondin type 1 motif, 13 isoform2 preproprotein [Homosapiens]; (272:) ADAM metallopeptidase with thrombospondin type 1 motif,13 isoform3 preproprotein [Homo sapiens]; (273:) ADAM metallopeptidasewith thrombospondin type 1 motif, 1 preproprotein [Homo sapiens]; (274:)ADAM metallopeptidase with thrombospondin type 1 motif, 2 isoform 1preproprotein [Homo sapiens]; (275:) ADAM metallopeptidase withthrombospondin type 1 motif, 2 isoform 2 [Homo sapiens]; (276:) ADAMmetallopeptidase with thrombospondin type 1 motif, 3proprotein [Homosapiens]; (277:) ADAM metallopeptidase with thrombospondin type 1 motif,4preproprotein [Homo sapiens]; (278:) ADAM metallopeptidase withthrombospondin type 1 motif, 5preproprotein [Homo sapiens]; (279:) ADAMmetallopeptidase with thrombospondin type 1 motif, 8preproprotein [Homosapiens]; (280:) ADAM10 [Homo sapiens]; (281:) ADAMTS-13 precursor (Adisintegrin and metalloproteinase with thrombospondin motifs 13)(ADAM-TS13) (ADAM-TS13) (von Willebrand factor-cleaving protease)(vWF-cleaving protease) (vWF-CP); (282:) ADAMTS-14 precursor (Adisintegrin and metalloproteinase with thrombospondin motifs 14)(ADAM-TS14) (ADAM-TS14); (283:) ADAMTS-2 precursor (A disintegrin andmetalloproteinase with thrombospondin motifs 2) (ADAM-TS 2) (ADAM-TS2)(Procollagen I/II amino propeptide-processing enzyme) (Procollagen IN-proteinase) (PC I-NP) (Procollagen N-endopeptidase) (pNPI); (284:)ADAMTS-3 precursor (A disintegrin and metalloproteinase withthrombospondin motifs 3) (ADAM-TS 3) (ADAM-TS3) (Procollagen II aminopropeptide-processing enzyme) (Procollagen II N-proteinase) (PC II-NP);(285:) adaptor-related protein complex 2, alpha 1 subunit isoform 1[Homo sapiens]; (286:) adaptor-related protein complex 2, alpha 1subunit isoform 2 [Homo sapiens]; (287:) Adeninephosphoribosyltransferase (APRT); (288:) adeninephosphoribosyltransferase isoform a [Homo sapiens]; (289:) adeninephosphoribosyltransferase isoform b [Homo sapiens]; (290:) Adenosine A1receptor; (291:) Adenosine A2a receptor; (292:) Adenosine A2b receptor;(293:) Adenosine A3 receptor; (294:) adenosine deaminase [Homo sapiens];(295:) adenosine deaminase variant [Homo sapiens]; (296:) adenosinedeaminase, RNA-specific isoform a [Homo sapiens]; (297:) adenosinedeaminase, RNA-specific isoform b [Homo sapiens]; (298:) adenosinedeaminase, RNA-specific isoform c [Homo sapiens]; (299:) adenosinedeaminase, RNA-specific isoform d [Homo sapiens]; (300:) adenosinekinase isoform a [Homo sapiens]; (301:) adenosine kinase isoform b [Homosapiens]; (302:) adenosine monophosphate deaminase 1 (isoform M) [Homosapiens]; (303:) adenylate cyclase (EC 4.6.1.1)—human (fragment); (304:)adenylate cyclase 2 [Homo sapiens]; (305:) adenylate cyclase 3 [Homosapiens]; (306:) adenylate cyclase 5 [Homo sapiens]; (307:) adenylatecyclase 6 isoform a [Homo sapiens]; (308:) adenylate cyclase 6 isoform b[Homo sapiens]; (309:) adenylate cyclase 7 [Homo sapiens]; (310:)adenylate cyclase 8 [Homo sapiens]; (311:) adenylate cyclase 9 [Homosapiens]; (312:) adenylate cyclase activating polypeptide 1 (pituitary)receptor type I precursor [Homo sapiens]; (313:) Adenylate cyclase type1 (Adenylate cyclase type 1) (ATP pyrophosphate-lyase 1)(Ca(2+)/calmodulin-activated adenylylcyclase); (314:) Adenylate cyclasetype 2 (Adenylate cyclase type 11) (ATP pyrophosphate-lyase 2) (Adenylylcyclase 2); (315:) Adenylate cyclase type 3 (Adenylate cyclase type III)(Adenylatecyclase, olfactive type) (ATP pyrophosphate-lyase 3)(Adenylylcyclase 3) (AC-III) (AC3); (316:) Adenylate cyclase type 4(Adenylate cyclase type IV) (ATP pyrophosphate-lyase 4) (Adenylylcyclase 4); (317:) Adenylate cyclase type 5 (Adenylate cyclase type V)(ATP pyrophosphate-lyase 5) (Adenylyl cyclase 5); (318:) Adenylatecyclase type 6 (Adenylate cyclase type VI) (ATP pyrophosphate-lyase 6)(Ca(2+)-inhibitable adenylyl cyclase); (319:) Adenylate cyclase type 8(Adenylate cyclase type VIII) (ATP pyrophosphate-lyase 8)(Ca(2+)/calmodulin-activated adenylylcyclase); (320:) Adenylate cyclasetype 9 (Adenylate cyclase type IX) (ATP pyrophosphate-lyase 9) (Adenylylcyclase 9); (321:) adenylate kinase 1 [Homo sapiens]; (322:) adenylatekinase 2 isoform a [Homo sapiens]; (323:) adenylate kinase 2 isoform b[Homo sapiens]; (324:) Adenylate kinase isoenzyme 1 (ATP-AMPtransphosphorylase) (AK1) (Myokinase); (325:) Adenylate kinase isoenzyme2, mitochondrial (ATP-AMP transphosphorylase); (326:) Adenylate kinaseisoenzyme 5 (ATP-AMP transphosphorylase); (327:) Adenylate kinaseisoenzyme 6 (ATP-AMP transphosphorylase 6); (328:) Adenylosuccinatelyase (Adenylosuccinase) (ASL) (ASASE); (329:) adenylosuccinate lyase[Homo sapiens]; (330:) adenylosuccinate synthase [Homo sapiens]; (331:)adhesion regulating molecule 1 precursor [Homo sapiens]; (332:)adiponectin precursor [Homo sapiens]; (333:) Adiponectin receptorprotein 1 (Progestin and adipoQ receptor family member I); (334:)Adiponectin receptor protein 2 (Progestin and adipoQ receptor familymember 11); (335:) “Adiponutrin (iPLA2-epsilon) (Calcium-independentphospholipase A2-epsilon) (Patatin-like phospholipase domain-containingprotein3) [Includes:) Triacylglycerol lipase;AcylglycerolO-acyltransferase].”; (336:) ADP-ribosyl cyclase 1 (CyclicADP-ribose hydrolase 1) (cADPr hydrolase 1) (Lymphocyte differentiationantigen CD38) (T10) (Acutelymphoblastic leukemia cells antigen CD38);(337:) ADP-ribosylarginine hydrolase [Homo sapiens]; (338:)ADP-ribosylation factor binding protein 2 [Homo sapiens]; (339:)ADP-ribosyltransferase 5 precursor [Homo sapiens]; (340:) adrenal glandprotein AD-004 [Homo sapiens]; (341:) Adrenocorticotropic hormonereceptor (ACTH receptor) (ACTH-R) (Melanocortin receptor 2) (MC2-R)(Adrenocorticotropin receptor); (342:) Adrenomedullin receptor (AM-R);(343:) advanced glycosylation end product-specific receptor isoform 1precursor [Homo sapiens]; (344:) advanced glycosylation endproduct-specific receptor isoform 2precursor [Homo sapiens]; (345:)aggrecanase 1 [Homo sapiens]; (346:) AHCYL1 protein [Homo sapiens];(347:) AICAR formyl transferase/IMP cyclohydrolase bifunctional enzyme;(348:) AK001663 hypothetical protein [Homo sapiens]; (349:) A-kinaseanchor protein 10 precursor [Homo sapiens]; (350:) A-kinase anchorprotein 5 (A-kinase anchor protein 79 kDa) (AKAP79) (cAMP-dependentprotein kinase regulatory subunit 11 high affinity-binding protein)(H21); (351:) A-kinase anchor protein 7 isoform alpha [Homo sapiens];(352:) A-kinase anchor protein 7 isoform beta [Homo sapiens]; (353:)A-kinase anchor protein 7 isoform gamma [Homo sapiens]; (354:) A-kinaseanchor protein 8 [Homo sapiens]; (355:) alanyl-tRNA synthetase [Homosapiens]; (356:) albumin precursor [Homo sapiens]; (357:) Alcoholdehydrogenase [NADP+] (Aldehyde reductase) (Aldo-ketoreductase family 1member A1); (358:) Alcohol dehydrogenase 1 B (Alcohol dehydrogenase betasubunit); (359:) alcohol dehydrogenase 1B (class I), beta polypeptide[Homo sapiens]; (360:) Alcohol dehydrogenase 4 (Alcohol dehydrogenaseclass II pi chain); (361:) Alcohol dehydrogenase class 4 mu/sigma chain(Alcohol dehydrogenase class IV mu/sigma chain) (Retinol dehydrogenase)(Gastric alcohol dehydrogenase); (362:) alcohol dehydrogenase pisubunit; (363:) alcohol dehydrogenase, iron containing, 1 isoform 1[Homo sapiens]; (364:) alcohol dehydrogenase, iron containing, 1 isoform2 [Homo sapiens]; (365:) “alcohol sulfotransferase; hydroxysteroidsulfotransferase [Homo sapiens].”; (366:) aldehyde dehydrogenase (NAD+)[Homo sapiens]; (367:) aldehyde dehydrogenase 1 (EC 1.2.1.3); (368:)aldehyde dehydrogenase 1 family, member L1 [Homo sapiens]; (369:)aldehyde dehydrogenase 1A1 [Homo sapiens]; (370:) aldehyde dehydrogenase1A2 isoform 1 [Homo sapiens]; (371:) aldehyde dehydrogenase 1A2 isoform2 [Homo sapiens]; (372:) aldehyde dehydrogenase 1A2 isoform 3 [Homosapiens]; (373:) Aldehyde dehydrogenase 1A3 (Aldehyde dehydrogenase 6)(Retinaldehyde dehydrogenase 3) (RALDH-3); (374:) aldehyde dehydrogenase1B1 precursor [Homo sapiens]; (375:) aldehyde dehydrogenase 2 (EC1.2.1.3); (376:) aldehyde dehydrogenase 3 family, member A1 [Homosapiens]; (377:) aldehyde dehydrogenase 4A1 precursor [Homo sapiens];(378:) aldehyde dehydrogenase 5A1 precursor, isoform 1 [Homo sapiens];(379:) aldehyde dehydrogenase 5A1 precursor, isoform 2 [Homo sapiens];(380:) aldehyde dehydrogenase 6A1 precursor [Homo sapiens]; (381:)aldehyde dehydrogenase 8A1 isoform 1 [Homo sapiens]; (382:) aldehydedehydrogenase 8A1 isoform 2 [Homo sapiens]; (383:) aldehydedehydrogenase 9A1 [Homo sapiens]; (384:) Aldehyde dehydrogenase, dimericNADP-preferring (ALDH class 3) (ALDHIII); (385:) Aldehyde dehydrogenase,mitochondrial precursor (ALDH class 2) (ALDHI) (ALDH-E2); (386:)Aldehyde Reductase; (387:) Aldo-keto reductase family 1 memberC3(Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase)(3-alpha-hydroxysteroid dehydrogenase type 2) (3-alpha-HSD type 2)(3-alpha-HSD type 11, brain) (Prostaglandin F synthase) (PGFS)(Estradiol 17-beta-dehydrogenase) (17-beta-hydroxysteroid dehydrogenasetype 5) (17-beta-HSD 5) (Chlordecone reductase homolog HAKRb) (HA1753)(Dihydrodiol dehydrogenase type I) (Dihydrodiol dehydrogenase 3) (DD3)(DD-3); (388:) aldo-keto reductase family 1, member A1 [Homo sapiens];(389:) aldo-keto reductase family 1, member B1 [Homo sapiens]; (390:)aldo-keto reductase family 1, member C1 [Homo sapiens]; (391:) aldo-ketoreductase family 1, member C2 [Homo sapiens]; (392:) aldo-keto reductasefamily 1, member C3 [Homo sapiens]; (393:) aldo-keto reductase family 1,member C4 [Homo sapiens]; (394:) aldo-keto reductase family 1, member D1[Homo sapiens]; (395:) aldolase A [Homo sapiens]; (396:) aldolase B[Homo sapiens]; (397:) Aldose reductase (AR) (Aldehyde reductase);(398:) Aldose Reductase (E.C.1.1.1.21) Mutant With Cys 298 Replaced BySer (C298s) Complex With Nadph; (399:) Aldose Reductase (E.C.1.1.1.21)Mutant With Tyr 48 Replaced By His(Y48h) Complexed With Nadp+ AndCitrate; (400:) ALK tyrosine kinase receptor precursor (Anaplasticlymphoma kinase) (CD246 antigen); (401:) Alkaline ceramidase 1 (AlkalineCDase-1) (Alk CDase 1) (Acylsphingosine deacylase 3) (N-acylsphingosineamidohydrolase 3); (402:) Alkaline phosphatase, placental type precursor(PLAP-1) (Reganisozyme); (403:) Alkaline phosphatase, tissue-nonspecificisozyme precursor (AP-TNAP) (Liver/bone/kidney isozyme) (TNSALP); (404:)Alkaline phytoceramidase (aPHC) (Alkaline ceramidase)(Alkalinedihydroceramidase SB89); (405:) alkaline phytoceramidase [Homosapiens]; (406:) alkyldihydroxyacetone phosphate synthase precursor[Homo sapiens]; (407:) Alkyldihydroxyacetonephosphate synthase,peroxisomal precursor (Alkyl-DHAP synthase) (Alkylglycerone-phosphatesynthase) (Aging-associated protein 5); (408:) alpha (1, 2)fucosyltransferase [Homo sapiens]; (409:) alpha 1 type I collagenpreproprotein [Homo sapiens]; (410:) alpha 1 type II collagen isoform 1precursor [Homo sapiens]; (411:) alpha 1 type II collagen isoform 2precursor [Homo sapiens]; (412:) alpha 1,2-mannosidase [Homo sapiens];(413:) alpha 1,4-galactosyltransferase [Homo sapiens]; (414:) alpha2,3-sialyltransferase III isoform A7 [Homo sapiens]; (415:) alpha2,3-sialyltransferase III isoform A8 [Homo sapiens]; (416:) alpha2,3-sialyltransferase III type D2+26 [Homo sapiens]; (417:) alphagalactosidase A; (418:) alpha isoform of regulatory subunit A, proteinphosphatase 2 [Homo sapiens]; (419:) alpha isoform of regulatory subunitB55, protein phosphatase 2 [Homo sapiens]; (420:) alpha mannosidase 11;(421:) Alpha platelet-derived growth factor receptor precursor(PDGF-R-alpha) (CD140a antigen); (422:) alpha(1,2)fucosyltransferase[Homo sapiens]; (423:) Alpha-(1,3)-fucosyltransferase (Galactoside3-L-fucosyltransferase) (Fucosyltransferase 6) (FUCT-VI); (424:)alpha/beta hydrolase domain containing protein 1 [Homo sapiens]; (425:)alpha-1 antitrypsin [Homo sapiens]; (426:) alpha-1 antitrypsin variant[Homo sapiens]; (427:) alpha-1,3(6)-mannosylglycoproteinbeta-1,6-N-acetyl-glucosaminyltransferase [Homo sapiens]; (428:)Alpha-1,4-N-acetylglucosaminyltransferase (Alpha4GnT); (429:) Alpha-1Aadrenergic receptor (Alpha 1A-adrenoceptor) (Alpha1A-adrenoreceptor)(Alpha-1C adrenergic receptor) (Alpha adrenergic receptor 1c); (430:)Alpha-1-antichymotrypsin precursor (ACT)[Contains:Alpha-1-antichymotrypsin His-Pro-less]; (431:) Alpha-1Badrenergic receptor (Alpha 1B-adrenoceptor) (Alpha1B-adrenoreceptor);(432:) Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor)(Alpha1D-adrenoreceptor) (Alpha-1A adrenergic receptor) (Alphaadrenergic receptor 1a); (433:) Alpha-2A adrenergic receptor (Alpha-2Aadrenoceptor) (Alpha-2A adreno receptor) (Alpha-2AAR) (Alpha-2adrenergic receptor subtype C10); (434:) Alpha-2B adrenergic receptor(Alpha-2B adrenoceptor) (Alpha-2B adrenoreceptor) (Alpha-2 adrenergicreceptor subtype C2); (435:) Alpha-2C adrenergic receptor (Alpha-2Cadrenoceptor) (Alpha-2C adrenoreceptor) (Alpha-2 adrenergic receptorsubtype C4); (436:) Alpha-2-macroglobulin precursor (Alpha-2-M); (437:)alpha-2-macroglobulin precursor [Homo sapiens]; (438:) alpha-2-plasmininhibitor [Homo sapiens]; (439:) alpha2-subunit of soluble guanylylcyclase [Homo sapiens]; (440:) alpha-aminoadipate semialdehyde synthase[Homo sapiens]; (441:) “Alpha-aminoadipic semialdehyde synthase,mitochondrial precursor (LKR/SDH) [Includes:) Lysine ketoglutaratereductase (LOR) (LKR); Saccharopine dehydrogenase (SDH)].”; (442:)Alpha-enolase (2-phospho-D-glycerate hydro-lyase) (Non-neuralenolase)(NNE) (Enolase 1) (Phosphopyruvate hydratase) (C-myc promoter-bindingprotein) (MBP-1) (MPB-1) (Plasminogen-binding protein); (443:)alpha-galactosidase A [Homo sapiens]; (444:) alpha-galactosidase Aprecursor (EC 3.2.1.22); (445:) Alpha-galactosidase A precursor(Melibiase) (Alpha-D-galactosidegalactohydrolase) (Alpha-D-galactosidaseA) (Agalsidase alfa); (446:) alpha-galactosidase; (447:) alpha-keto aciddehydrogenase precursor; (448:) “alpha-ketoglutarate dehydrogenasecomplex dihydrolipoylsuccinyltransferase; KGDHC E2k component [Homosapiens].”; (449:) alpha-KG-E2 [Homo sapiens]; (450:) Alpha-lactalbuminprecursor (Lactose synthase B protein); (451:) alpha-L-iduronidaseprecursor [Homo sapiens]; (452:) Alpha-L-iduronidase precursor; (453:)alpha-methylacyl-CoA racemase isoform 1 [Homo sapiens]; (454:)alpha-methylacyl-CoA racemase isoform 2 [Homo sapiens]; (455:)alpha-N-acetylgalactosaminidase precursor [Homo sapiens]; (456:)alpha-N-acetylglucosaminidase precursor [Homo sapiens]; (457:)alpha-N-acetylglucosaminidase; (458:) Alpha-N-acetylneuraminidealpha-2,8-sialyltransferase (Ganglioside GD3 synthase) (Ganglioside GT3synthase) (Alpha-2,8-sialyltransferase 8A) (ST8Sia I); (459:)alpha-synuclein isoform NACP112 [Homo sapiens]; (460:) alpha-synucleinisoform NACP140 [Homo sapiens]; (461:) amiloride binding protein [Homosapiens]; (462:) Amiloride binding protein 1 (amine oxidase(copper-containing))[Homo sapiens]; (463:) amiloride binding protein 1precursor [Homo sapiens]; (464:) amiloride-binding protein 1 (amineoxidase (copper-containing))[Homo sapiens]; (465:) amiloride-bindingprotein; (466:)

Amiloride-sensitive amine oxidase [copper-containing] precursor (Diamineoxidase) (DAO) (Amiloride-binding protein) (ABP) (Histaminase) (Kidneyamine oxidase) (KAO); (467:) amine oxidase (flavin containing) domain 2isoform b [Homo sapiens]; (468:) amine oxidase (flavin-containing) [Homosapiens]; (469:) Amine oxidase [flavin-containing] A (Monoamine oxidasetype A) (MAO-A); (470:) amine oxidase, copper containing 2(retina-specific) [Homo sapiens]; (471:) amine oxidase, coppercontaining 2 isoform a [Homo sapiens]; (472:) amine oxidase, coppercontaining 2 isoform b [Homo sapiens]; (473:) Amine oxidase, coppercontaining 3 (vascular adhesion protein 1)[Homo sapiens]; (474:) amineoxidase, copper containing 3 precursor [Homo sapiens]; (475:) amino-acidN-acetyltransferase (EC 2.3.1.1)-human; (476:) aminoacylase 1 [Homosapiens]; (477:) aminoadipate-semialdehydedehydrogenase-phosphopantetheinyltransferase [Homo sapiens]; (478:)aminoadipate-semialdehyde synthase [Homo sapiens]; (479:)aminocarboxymuconate semialdehyde decarboxylase [Homo sapiens]; (480:)aminolevulinate delta-synthase 1 [Homo sapiens]; (481:) aminolevulinate,delta, synthase 1 [Homo sapiens]; (482:) Aminolevulinate, delta-,synthase 1 [Homo sapiens]; (483:) aminolevulinate, delta-, synthase 2isoform a [Homo sapiens]; (484:) aminolevulinate, delta-, synthase 2isoform b [Homo sapiens]; (485:) aminolevulinate, delta-, synthase 2isoform c [Homo sapiens]; (486:) aminolevulinate, delta-, synthase 2isoform d [Homo sapiens]; (487:) aminomethyltransferase (glycinecleavage system protein T) [Homo sapiens]; (488:) Aminopeptidase N(hAPN) (Alanyl aminopeptidase) (Microsomalaminopeptidase)(Aminopeptidase M) (gp150) (Myeloid plasma membrane glycoprotein CD13)(CD13 antigen); (489:) Aminopeptidase O (AP-O); (490:) aminopeptidasepuromycin sensitive [Homo sapiens]; (491:) AMP deaminase 3 (AMPdeaminase isoform E) (Erythrocyte AMP deaminase); (492:) AMP-activatedprotein kinase alpha 2 catalytic subunit [Homo sapiens]; (493:)AMP-activated protein kinase beta 1 non-catalytic subunit [Homosapiens]; (494:) AMP-activated protein kinase beta 2 non-catalyticsubunit [Homo sapiens]; (495:) AMP-activated protein kinase gamma2subunit isoform a [Homo sapiens]; (496:) AMP-activated protein kinasegamma2 subunit isoform b [Homo sapiens]; (497:) AMP-activated proteinkinase gamma2 subunit isoform c [Homo sapiens]; (498:) AMP-activatedprotein kinase, noncatalytic gamma-1 subunit isoform1 [Homo sapiens];(499:) AMP-activated protein kinase, noncatalytic gamma-1 subunitisoform2 [Homo sapiens]; (500:) AMP-activated protein kinase,non-catalytic gamma-3 subunit [Homo sapiens]; (501:) AMP-binding enzyme,33217 [Homo sapiens]; (502:) amphiregulin preproprotein [Homo sapiens];(503:) “amylase, alpha 1A; salivary precursor [Homo sapiens].”; (504:)Amylo-1,6-glucosidase, 4-alpha-glucanotransferase (glycogen debranchingenzyme, glycogen storage disease type III) [Homo sapiens]; (505:)amylo-1,6-glucosidase, 4-alpha-glucanotransferase isoform 1 [Homosapiens]; (506:) amylo-1,6-glucosidase, 4-alpha-glucanotransferaseisoform 2 [Homo sapiens]; (507:) amylo-1,6-glucosidase,4-alpha-glucanotransferase isoform 3 [Homo sapiens]; (508:) “Amyloidbeta A4 protein precursor (APP) (ABPP) (Alzheimer disease amyloidprotein) (Cerebral vascular amyloid peptide) (CVAP) (Protease nexin-II)(PN-II) (APPI) (PreA4) [Contains:) Soluble APP-alpha (S-APP-alpha);Soluble APP-beta (S-APP-beta); C99; Beta-amyloid protein 42(Beta-APP42); Beta-amyloid protein 40(Beta-APP40); C83; P3(42); P3(40);Gamma-CTF (59) (Gamma-secretase C-terminal fragment 59) (Amyloidintracellular domain 59) (AID(59)); Gamma-CTF(57) (Gamma-secretaseC-terminal fragment 57) (Amyloid intracellular domain 57) (AID(57));Gamma-CTF(50) (Gamma-secretase C-terminal fragment 50) (Amyloidintracellular domain 50) (AID(50)); C31].”; (509:) amyloid beta A4protein precursor, isoform a [Homo sapiens]; (510:) amyloid beta A4protein precursor, isoform b [Homo sapiens]; (511:) amyloid beta A4protein precursor, isoform c [Homo sapiens]; (512:) Amyloid betaprecursor protein binding protein 1 [Homo sapiens]; (513:) amyloid betaprecursor protein-binding protein 1 isoform a [Homo sapiens]; (514:)amyloid beta precursor protein-binding protein 1 isoform b [Homosapiens]; (515:) amyloid beta precursor protein-binding protein 1isoform c [Homo sapiens]; (516:) amyloid precursor protein-bindingprotein 1 (APP-B1) [Homo sapiens]; (517:) amyloid precursorprotein-binding protein 1; (518:) anaphase promoting complex subunit 1[Homo sapiens]; (519:) anaphase promoting complex subunit 10 [Homosapiens]; (520:) Anaphase-promoting complex subunit 11 (APC11)(Cyclosome subunit 11) (Hepatocellular carcinoma-associated RING fingerprotein); (521:) anaphase-promoting complex subunit 2 [Homo sapiens];(522:) anaphase-promoting complex subunit 4 [Homo sapiens]; (523:)anaphase-promoting complex subunit 5 [Homo sapiens]; (524:)anaphase-promoting complex subunit 7 [Homo sapiens]; (525:) Androgenreceptor (Dihydrotestosterone receptor); (526:) androgen receptorisoform 1 [Homo sapiens]; (527:) androgen receptor isoform 2 [Homosapiens]; (528:) androgen-regulated short-chain dehydrogenase/reductase1 [Homo sapiens]; (529:) Angiogenin precursor (Ribonuclease 5) (RNase5); (530:) Angiopoietin-1 receptor precursor (Tyrosine-protein kinasereceptor TIE-2) (hTIE2) (Tyrosine-protein kinase receptor TEK) (p140TEK) (Tunica interna endothelial cell kinase) (CD202b antigen); (531:)angiotensin converting enzyme (EC 3.4.15.1); (532:) angiotensinconverting enzyme 2 [Homo sapiens]; (533:) angiotensin converting enzymeprecursor (EC 3.4.15.1); (534:) angiotensin converting enzyme-likeprotein [Homo sapiens]; (535:) angiotensin I converting enzyme(peptidyl-dipeptidase A) 1 [Homo sapiens]; (536:) Angiotensin Iconverting enzyme (peptidyl-dipeptidase A) 2 [Homo sapiens]; (537:)angiotensin I converting enzyme [Homo sapiens]; (538:) angiotensin Iconverting enzyme 2 precursor [Homo sapiens]; (539:) angiotensin Iconverting enzyme isoform I precursor [Homo sapiens]; (540:) angiotensinI converting enzyme isoform 1 precursor variant [Homo sapiens]; (541:)angiotensin I converting enzyme isoform 2 precursor [Homo sapiens];(542:) angiotensin I converting enzyme isoform 3 precursor [Homosapiens]; (543:) “angiotensin I converting enzyme precursor;dipeptidylcarboxypeptidase 1 [Homo sapiens].”; (544:) “angiotensin Iconverting enzyme precursor; dipeptidylcarboxypeptidase 1; kinase II[Homo sapiens].”; (545:) angiotensin 1-converting enzyme [Homo sapiens];(546:) angiotensin I-converting enzyme precursor (EC 3.4.15.1); (547:)angiotensin II receptor type-1 (clone HATR1GH)—human (fragment); (548:)angiotensin II receptor, type 1 [Homo sapiens]; (549:) angiotensin 11receptor, type 2 [Homo sapiens]; (550:) angiotensin-converting enzyme[Homo sapiens]; (551:) angiotensin-converting enzyme 2 [Homo sapiens];(552:) Angiotensin-converting enzyme 2 precursor (ACE-relatedcarboxypeptidase) (Angiotensin-converting enzyme homolog) (ACEH); (553:)Angiotensin-converting enzyme, somatic isoform precursor (Dipeptidylcarboxypeptidase I) (Kininase II) (CD143 antigen)[Contains:)Angiotensin-converting enzyme, somatic isoform, soluble form]; (554:)Angiotensin-converting enzyme, testis-specific isoform precursor (ACE-T)(Dipeptidyl carboxypeptidase I) (Kininase II)[Contains:Angiotensin-converting enzyme, testis-specific isoform,soluble form]; (555:) “Angiotensinogen precursor [Contains:)Angiotensin-1 (Angiotensin I) (Ang I); Angiotensin-2 (Angiotensin II)(Ang II); Angiotensin-3(Angiotensin III) (Ang III)(Des-Asp[1]-angiotensin II)].”; (556:) angiotensinogen preproprotein[Homo sapiens]; (557:) Annexin A4 (Annexin IV) (Lipocortin IV)(Endonexin I) (Chromobindin-4) (Protein II) (P32.5) (Placentalanticoagulant protein II) (PAP-II) (PP4-X) (35-beta calcimedin)(Carbohydrate-binding protein P33/P41) (P33/41); (558:) Annexin A5(Annexin V) (Lipocortin V) (Endonexin II) (CalphobindinI) (CBP-I)(Placental anticoagulant protein I) (PAP-I) (PP4) (Thromboplastininhibitor) (Vascular anticoagulant-alpha) (VAC-alpha) (Anchorin CII);(559:) anthracycline-associated resistance ARX [Homo sapiens]; (560:)Anthrax toxin receptor 1 precursor (Tumor endothelial marker 8); (561:)Anthrax toxin receptor 2 precursor (Capillary morphogenesis gene2protein) (CMG-2); (562:) Anti-Muellerian hormone type-2 receptorprecursor (Anti-Muellerian hormone type II receptor) (AMH type IIreceptor) (MIS type II receptor) (MISRII) (MRII); (563:) antioxidantenzyme AOE37-2 [Homo sapiens]; (564:) antioxidant enzyme B166 [Homosapiens]; (565:) AP2-associated protein kinase 1 (Adaptor-associatedkinase 1); (566:) APC11 anaphase promoting complex subunit 11 isoform 1[Homo sapiens]; (567:) APC11 anaphase promoting complex subunit 11isoform 2 [Homo sapiens]; (568:) Apelin receptor (G-protein coupledreceptor APJ) (Angiotensin receptor-like 1) (HG11); (569:) APEX nuclease(multifunctional DNA repair enzyme) [Homo sapiens]; (570:) APEX nuclease(multifunctional DNA repair enzyme) 1 [Homo sapiens]; (571:) APG10autophagy 10-like [Homo sapiens]; (572:) APG12 autophagy 12-like [Homosapiens]; (573:) Apg3p [Homo sapiens]; (574:) APG4 autophagy 4 homolog Bisoform a [Homo sapiens]; (575:) APG4 autophagy 4 homolog β isoform b[Homo sapiens]; (576:) APG5 autophagy 5-like [Homo sapiens]; (577:) APG7autophagy 7-like [Homo sapiens]; (578:) APOBEC1 complementation factor(APOBEC1-stimulating protein); (579:) apobec-1 complementation factorisoform 1 [Homo sapiens]; (580:) apobec-1 complementation factor isoform2 [Homo sapiens]; (581:) apobec-1 complementation factor isoform 3 [Homosapiens]; (582:) APOBEC-1 stimulating protein [Homo sapiens]; (583:)Apolipoprotein A-I precursor (Apo-AI) (ApoA-I) [Contains:ApolipoproteinA-I (1-242)]; (584:) apolipoprotein A-II preproprotein [Homo sapiens];(585:) apolipoprotein B mRNA editing enzyme [Homo sapiens]; (586:)apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G[Homosapiens]; (587:) apolipoprotein B mRNA editing enzyme complex-1 [Homosapiens]; (588:) apolipoprotein B mRNA editing enzyme, catalyticpolypeptide 1; (589:) apolipoprotein B mRNA editing enzyme, catalyticpolypeptide-like 2 [Homo sapiens]; (590:) apolipoprotein B mRNA editingenzyme, catalytic polypeptide-like 2variant [Homo sapiens]; (591:)Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A[Homosapiens]; (592:) apolipoprotein B mRNA editing enzyme, catalyticpolypeptide-like 3B[Homo sapiens]; (593:) apolipoprotein B mRNA editingenzyme, catalytic polypeptide-like 3C [Homo sapiens]; (594:)apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3Cvariant [Homo sapiens]; (595:) apolipoprotein B mRNA editing enzyme,catalytic polypeptide-like 3D[Homo sapiens]; (596:) Apolipoprotein BmRNA editing enzyme, catalytic polypeptide-like 3F[Homo sapiens]; (597:)apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3Fisoform a [Homo sapiens]; (598:) apolipoprotein B mRNA editing enzyme,catalytic polypeptide-like 3F isoform b [Homo sapiens]; (599:)apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G[Homosapiens]; (600:) Apolipoprotein B mRNA editing enzyme, catalyticpolypeptide-like 3H[Homo sapiens]; (601:) apolipoprotein B mRNA editingenzyme, catalytic polypeptide-like 4(putative) [Homo sapiens]; (602:)apolipoprotein B precursor [Homo sapiens]; (603:) apolipoprotein C-IIprecursor [Homo sapiens]; (604:) apolipoprotein D precursor [Homosapiens]; (605:) apolipoprotein E precursor [Homo sapiens]; (606:)apoptotic caspase Mch5-beta [Homo sapiens]; (607:) apoptotic cysteineprotease Mch5 isoform alpha; (608:) apoptotic cysteine protease proMch4;(609:) aprataxin isoform a [Homo sapiens]; (610:) aprataxin isoform b[Homo sapiens]; (611:) aprataxin isoform c [Homo sapiens]; (612:)aprataxin isoform d [Homo sapiens]; (613:) apurinic/apyrimidinicendonuclease; (614:) aquaporin 12A [Homo sapiens]; (615:) arachidonate12-lipoxygenase [Homo sapiens]; (616:) arachidonate 15-lipoxygenase[Homo sapiens]; (617:) arachidonate 5-lipoxygenase [Homo sapiens];(618:) arachidonate 5-lipoxygenase-activating protein [Homo sapiens];(619:) Archaemetzincin-1 (Archeobacterial metalloproteinase-like protein1); (620:) Archaemetzincin-2 (Archeobacterial metalloproteinase-likeprotein2); (621:) arginase, type I [Homo sapiens]; (622:) Argininedecarboxylase (ARGDC) (ADC) (Ornithine decarboxylase-like protein)(ODC-paralogue) (ODC-p); (623:) arginine decarboxylase [Homo sapiens];(624:) arginine methyltransferase 6 [Homo sapiens]; (625:)argininosuccinate lyase isoform 1 [Homo sapiens]; (626:)argininosuccinate lyase isoform 2 [Homo sapiens]; (627:)argininosuccinate lyase isoform 3 [Homo sapiens]; (628:) arginylaminopeptidase (aminopeptidase B) [Homo sapiens]; (629:)arginyltransferase 1 isoform 1 [Homo sapiens]; (630:) arginyltransferase1 isoform 2 [Homo sapiens]; (631:) Ariadne homolog,ubiquitin-conjugating enzyme E2 binding protein, 1(Drosophila) [Homosapiens]; (632:) ariadne ubiquitin-conjugating enzyme E2 binding proteinhomolog 1 [Homo sapiens]; (633:) aromatase cytochrome P-450; (634:)aromatic decarboxylase [Homo sapiens]; (635:) Aromatic-L-amino-aciddecarboxylase (MDC) (DOPA decarboxylase) (DDC); (636:) Arsenitemethyltransferase(S-adenosyl-L-methionine:arsenic(III)methyltransferase) (Methylarsonitemethyltransferase); (637:)

Aryl hydrocarbon receptor precursor (Ah receptor) (AhR); (638:)Arylacetamide deacetylase (AADAC); (639:) arylalkylamineN-acetyltransferase [Homo sapiens]; (640:) arylamide acetylase 2 [Homosapiens]; (641:) Arylamine N-acetyltransferase 1 (Arylamide acetylase 1)(Monomorphic arylamine N-acetyltransferase) (MNAT) (N-acetyltransferasetype 1) (NAT-1); (642:) “Arylsulfatase A precursor (ASA)(Cerebroside-sulfatase) [Contains:Arylsulfatase A component B;Arylsulfatase A component C].”; (643:) arylsulfatase A precursor [Homosapiens]; (644:) arylsulfatase β isoform 1 precursor [Homo sapiens];(645:) arylsulfatase β isoform 2 precursor [Homo sapiens]; (646:)Arylsulfatase B precursor (ASB) (N-acetylgalactosamine-4-sulfatase)(G4S); (647:) Arylsulfatase E precursor (ASE); (648:) Arylsulfatase Fprecursor (ASF); (649:) Asialoglycoprotein receptor 1 (ASGPR 1)(ASGP-R1) (Hepatic lectin H1); (650:) Asialoglycoprotein receptor 2(ASGP-R2) (ASGPR2) (Hepatic lectin H2); (651:) asparagine-linkedglycosylation 12 [Homo sapiens]; (652:) aspartate aminotransferase 1[Homo sapiens]; (653:) aspartate aminotransferase 2 precursor [Homosapiens]; (654:) aspartoacylase [Homo sapiens]; (655:)aspartylglucosaminidase precursor [Homo sapiens]; (656:) aspartyl-tRNAsynthetase [Homo sapiens]; (657:) Astacin-like metalloendopeptidaseprecursor (Oocyte astacin) (Ovastacin); (658:) ataxin 3 isoform 1 [Homosapiens]; (659:) ataxin 3 isoform 2 [Homo sapiens]; (660:) ataxin 3isoform 3 [Homo sapiens]; (661:) Ataxin-3 (Machado-Joseph diseaseprotein 1) (Spinocerebellar ataxia type 3 protein); (662:) ATP citratelyase isoform 1 [Homo sapiens]; (663:) ATP citrate lyase isoform 2 [Homosapiens]; (664:) ATP specific succinyl CoA synthetase beta subunitprecursor [Homo sapiens]; (665:) ATP sulfurylase/APS kinase [Homosapiens]; (666:) ATP sulfurylase/APS kinase isoform SK2 [Homo sapiens];(667:) ATP synthase mitochondrial F1 complex assembly factor 1 isoform 1precursor [Homo sapiens]; (668:) ATP synthase mitochondrial F1 complexassembly factor 1 isoform 2 precursor [Homo sapiens]; (669:) ATPsynthase mitochondrial F1 complex assembly factor 2 [Homo sapiens];(670:) ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 isoform1 [Homo sapiens]; (671:) ATPase, Ca++ transporting, cardiac muscle, slowtwitch 2 isoform 2 [Homo sapiens]; (672:) ATPase, Ca++ transporting,fast twitch 1 isoform a [Homo sapiens]; (673:) ATPase, Ca++transporting,fast twitch 1 isoform b [Homo sapiens]; (674:) ATPase, Cu++transporting,alpha polypeptide [Homo sapiens]; (675:) ATPase, Cu++transporting, betapolypeptide isoform a [Homo sapiens]; (676:) ATPase, Cu++ transporting,beta polypeptide isoform b [Homo sapiens]; (677:) ATPase, H+transporting, lysosomal 14 kD, V1 subunit F [Homo sapiens]; (678:)ATPase, H+ transporting, lysosomal 21 kDa, V0 subunit b isoform 1 [Homosapiens]; (679:) ATPase, H+ transporting, lysosomal 21 kDa, V0 subunit bisoform 2 [Homo sapiens]; (680:) ATPase, H+ transporting, lysosomal 42kDa, V1 subunit C1 isoform A[Homo sapiens]; (681:) ATPase, H+transporting, lysosomal 42 kDa, V1 subunit C1 isoform B[Homo sapiens];(682:) ATPase, H+ transporting, lysosomal 50/57 kDa, V1 subunit H [Homosapiens]; (683:) ATPase, H+ transporting, lysosomal 50/57 kDa, V1subunit H isoform 1 [Homo sapiens]; (684:) ATPase, H+ transporting,lysosomal 50/57 kDa, V1 subunit H isoform 2 [Homo sapiens]; (685:)ATPase, H+ transporting, lysosomal 56/58 kDa, V1 subunit B1 [Homosapiens]; (686:) ATPase, H+ transporting, lysosomal 70 kD, V1 subunit A,isoform 1 [Homo sapiens]; (687:) ATPase, H+ transporting, lysosomal 9kDa, V0 subunit e1 [Homo sapiens]; (688:) ATPase, H+ transporting,lysosomal accessory protein 1 precursor[Homo sapiens]; (689:) ATPase, H+transporting, lysosomal V0 subunit a isoform 1 [Homo sapiens]; (690:)ATPase, H+ transporting, lysosomal V0 subunit a4 [Homo sapiens]; (691:)ATPase, H+ transporting, lysosomal, V0 subunit c [Homo sapiens]; (692:)ATPase, H+ transporting, lysosomal, V0 subunit d1 [Homo sapiens]; (693:)ATPase, H+ transporting, lysosomal, V1 subunit G2 isoform a [Homosapiens]; (694:) ATPase, H+ transporting, lysosomal, V1 subunit G2isoform b [Homo sapiens]; (695:) ATPase, H+ transporting, lysosomal, V1subunit G3 isoform a [Homo sapiens]; (696:) ATPase, H+ transporting,lysosomal, V1 subunit G3 isoform b [Homo sapiens]; (697:) ATPase, H+/K+exchanging, alpha polypeptide [Homo sapiens]; (698:) ATPase, H+/K+exchanging, beta polypeptide [Homo sapiens]; (699:) ATP-binding cassettesub-family B member 1 [Homo sapiens]; (700:) ATP-binding cassettetransporter sub-family C member 8(Sulfonylurea receptor 1); (701:)ATP-binding cassette transporter sub-family C member 9(Sulfonylureareceptor 2); (702:) ATP-citrate synthase (ATP-citrate (pro-S-)-lyase)(Citrate cleavage enzyme); (703:) ATP-dependent DNA helicase 2 subunit 1(ATP-dependent DNA helicasell 70 kDa subunit) (Lupus Ku autoantigenprotein p70) (Ku70) (70 kDa subunit of Ku antigen) (Thyroid-lupusautoantigen) (TLAA) (CTCbox-binding factor 75 kDa subunit) (CTCBF)(CTC75) (DNA-repair protein XRCC6); (704:) ATP-dependent DNA helicase 2subunit 2 (ATP-dependent DNA helicasell 80 kDa subunit) (Lupus Kuautoantigen protein p86) (Ku86) (Ku80) (86 kDa subunit of Ku antigen)(Thyroid-lupus autoantigen) (TLAA) (CTC box-binding factor 85 kDasubunit) (CTCBF) (CTC85) (Nuclear factor IV) (DNA-repair protein XRCC5);(705:) ATP-dependent DNA helicase II [Homo sapiens]; (706:)ATP-dependent DNA helicase 11, 70 kDa subunit [Homo sapiens]; (707:)Atrial natriuretic peptide clearance receptor precursor (ANP-C) (ANPRC)(NPR-C) (Atrial natriuretic peptide C-type receptor); (708:) Atrialnatriuretic peptide receptor A precursor (AN P-A) (AN PRA) (GC-A)(Guanylate cyclase) (NPR-A) (Atrial natriuretic peptide A-typereceptor); (709:) Atrial natriuretic peptide receptor B precursor(ANP-B) (ANPRB) (GC-B) (Guanylate cyclase B) (NPR-B) (Atrial natriureticpeptide B-type receptor); (710:) Atrial natriuteric peptide-convertingenzyme (pro-ANP-converting enzyme) (Corin) (Heart-specific serineproteinase ATC2) (Transmembrane protease, serine 10); (711:) Attractinprecursor (Mahogany homolog) (DPPT-L); (712:) AU RNA-bindingprotein/enoyl-Coenzyme A hydratase precursor [Homo sapiens]; (713:)Autocrine motility factor receptor precursor, isoform 1 (AMF receptor);(714:) Autocrine motility factor receptor, isoform 2 (AMF receptor)(gp78); (715:) autoimmune regulator AIRE isoform 1 [Homo sapiens];(716:) autoimmune regulator AIRE isoform 2 [Homo sapiens]; (717:)Autophagy-related protein 10 (APG10-like); (718:) Autophagy-relatedprotein 3 (APG3-like) (hApg3) (Protein PC3-96); (719:) Autophagy-relatedprotein 7 (APG7-like) (Ubiquitin-activating enzyme E1-like protein)(hAGP7); (720:) autotaxin isoform 1 preproprotein [Homo sapiens]; (721:)autotaxin isoform 2 preproprotein [Homo sapiens]; (722:) Azurocidinprecursor (Cationic antimicrobial protein CAP37) (Heparin-bindingprotein) (HBP); (723:) azurocidin, PUP=elastase homlog [human, PeptidePartial, 21 aa]; (724:) B- and T-lymphocyte attenuator precursor (B- andT-lymphocyte-associated protein) (CD272 antigen); (725:) B1 bradykininreceptor (BK-1 receptor) (B1R); (726:) B2 bradykinin receptor (BK-2receptor) (B2R); (727:) B3GAT1 [Homo sapiens]; (728:) B3GAT2 [Homosapiens]; (729:) B3GAT2 protein [Homo sapiens]; (730:) B3GAT3 protein[Homo sapiens]; (731:) baculoviral IAP repeat-containing 6 [Homosapiens]; (732:) Baculoviral IAP repeat-containing protein 6(Ubiquitin-conjugating BIR-domain enzyme apollon); (733:) Basicfibroblast growth factor receptor 1 precursor (FGFR-1) (bFGF-R)(Fms-like tyrosine kinase 2) (c-fgr) (CD331 antigen); (734:) BDNF/NT-3growth factors receptor precursor (Neurotrophic tyrosine kinase receptortype 2) (TrkB tyrosine kinase) (GP145-TrkB) (Trk-B); (735:) beclin 1[Homo sapiens]; (736:) beta adrenergic receptor kinase 1 [Homo sapiens];(737:) beta adrenergic receptor kinase 2 [Homo sapiens]; (738:) betaamyloid cleaving enzyme 2 [Homo sapiens]; (739:) beta isoform ofregulatory subunit A, protein phosphatase 2 isoform a [Homo sapiens];(740:) beta isoform of regulatory subunit A, protein phosphatase 2isoform b [Homo sapiens]; (741:) beta isoform of regulatory subunit B55,protein phosphatase 2 isoform a [Homo sapiens]; (742:) beta isoform ofregulatory subunit B55, protein phosphatase 2 isoform b [Homo sapiens];(743:) beta isoform of regulatory subunit B55, protein phosphatase 2isoform c [Homo sapiens]; (744:) beta isoform of regulatory subunit B55,protein phosphatase 2 isoform d [Homo sapiens]; (745:) beta isoform ofregulatory subunit B56, protein phosphatase 2A[Homo sapiens]; (746:)Beta klotho (BetaKlotho) (Klotho beta-like protein); (747:) Betaplatelet-derived growth factor receptor precursor (PDGF-R-beta) (CD140bantigen); (748:) beta(1,6)-N-acetylglucosaminyltransferase V isoform 1[Homo sapiens]; (749:) beta(1,6)-N-acetylglucosaminyltransferase Visoform 2 [Homo sapiens]; (750:) Beta,beta-carotene 9′,10′-dioxygenase(Beta-carotene dioxygenase 2) (B-diox-II); (751:) Beta-1 adrenergicreceptor (Beta-1 adrenoceptor) (Beta-1adrenoreceptor); (752:) beta-1,3galactosyltransferase-V [Homo sapiens]; (753:)Beta-1,3-galactosyl-O-glycosyl-glycoproteinbeta-1,6-N-acetylglucosaminyltransferase (Core 2 branching enzyme)(Core2-GlcNAc-transferase) (C2GNT) (Core 2 GNT); (754:)beta-1,3-galactosyl-O-glycosyl-glycoproteinbeta-1,6-N-acetylglucosaminyltransferase [Homo sapiens]; (755:)beta-1,3-galactosyltransferase [Homo sapiens]; (756:)Beta-1,3-galactosyltransferase 5 (Beta-1,3-GalTase 5) (Beta3Gal-T5)(b3Gal-T5) (UDP-galactose:beta-N-acetylglucosaminebeta-1,3-galactosyltransferase 5)(UDP-Gal:beta-GlcNAcbeta-1,3-galactosyltransferase 5) (Beta-3-Gx-T5);(757:) Beta-1,3-glucosyltransferase (Beta3Glc-T)(Beta-3-glycosyltransferase-like); (758:) Beta-1,3-glucuronyltransferase1 (glucuronosyltransferase P) [Homo sapiens]; (759:)beta-1,3-glucuronyltransferase 1 [Homo sapiens]; (760:)Beta-1,3-glucuronyltransferase 3 (glucuronosyltransferase 1) [Homosapiens]; (761:) beta-1,3-glucuronyltransferase 3 [Homo sapiens]; (762:)beta1,3-N-acetylglucosaminyltransferase 5 [Homo sapiens]; (763:)beta-1,3-N-acetylglucosaminyltransferase 6 [Homo sapiens]; (764:)“Beta-1,4-galactosyltransferase 1 (Beta-1,4-GalTase 1) (Beta4Gal-T1)(b4Gal-T1) (UDP-galactose:beta-N-acetylglucosaminebeta-1,4-galactosyltransferase 1)(UDP-Gal:beta-GlcNAcbeta-1,4-galactosyltransferase 1) [Includes:)Lactose synthase Aprotein; N-acetyllactosamine synthase (NaIsynthetase); Beta-N-acetylglucosaminylglycopeptidebeta-1,4-galactosyltransferase; Beta-N-acetylglucosaminyl-glycolipidbeta-1,4-galactosyltransferase].”; (765:) Beta-1,4-galactosyltransferase6 (Beta-1,4-GalTase 6) (Beta4Gal-T6) (b4Gal-T6)(UDP-galactose:beta-N-acetylglucosamine beta-1,4-galactosyltransferase6) (UDP-Gal:beta-GlcNAcbeta-1,4-galactosyltransferase 6) [Includes:)Lactosylceramidesynthase (LacCer synthase) (UDP-Gal:glucosylceramidebeta-1,4-galactosyltransferase)]; (766:)beta-1,4-N-acethylgalactosaminyltransferase [Homo sapiens]; (767:)beta-1,4-N-acetyl-galactosaminyl transferase 1 [Homo sapiens]; (768:)beta-1,6-N-acetylglucosaminyltransferase [Homo sapiens]; (769:)beta-1,6-N-acetylglucosaminyltransferase 2 [Homo sapiens]; (770:)beta-1,6-N-acetylglucosaminyltransferase 3 [Homo sapiens]; (771:)beta-1,6-N-acetylglucosaminyltransferase; (772:) Beta-2 adrenergicreceptor (Beta-2 adrenoceptor) (Beta-2adrenoreceptor); (773:) Beta-3adrenergic receptor (Beta-3 adrenoceptor) (Beta-3adrenoreceptor); (774:)beta-adrenergic-receptor kinase (EC 2.7.1.126) 2—human; (775:)Beta-Ala-His dipeptidase precursor (Carnosine dipeptidase 1) (CNDPdipeptidase 1) (Serum carnosinase) (Glutamate carboxypeptidase-likeprotein 2); (776:) beta-carotene 15, 15′-monooxygenase 1 [Homo sapiens];(777:) beta-carotene dioxygenase 2 isoform a [Homo sapiens]; (778:)beta-carotene dioxygenase 2 isoform b [Homo sapiens]; (779:)beta-D-galactosidase precursor (EC 3.2.1.23); (780:) Beta-galactosidaseprecursor (Lactase) (Acid beta-galactosidase); (781:) beta-galactosidaserelated protein precursor; (782:) Beta-galactosidase-related proteinprecursor (Beta-galactosidase-like protein) (S-Gal) (Elastin-bindingprotein) (EBP); (783:) Beta-hexosaminidase alpha chain precursor(N-acetyl-beta-glucosaminidase) (Beta-N-acetylhexosaminidase)(Hexosaminidase A); (784:) “Beta-hexosaminidase beta chain precursor(N-acetyl-beta-glucosaminidase) (Beta-N-acetylhexosaminidase)(Hexosaminidase B) (Cervical cancer proto-oncogene 7) (HCC-7)[Contains:)Beta-hexosaminidase beta-B chain; Beta-hexosaminidase beta-A chain].”;(785:) beta-hexosaminidase beta-chain {R to Q substitution at residue505, internal fragment} {EC 3.2.1.53} [human, skin fibroblasts, PeptidePartial Mutant, 23 aa]; (786:) betaine-homocysteine methyltransferase[Homo sapiens]; (787:) beta-mannosidase [Homo sapiens]; (788:)beta-polymerase; (789:) Beta-secretase 1 precursor (Beta-site APPcleaving enzyme 1) (Beta-site amyloid precursor protein cleavingenzyme 1) (Membrane-associated aspartic protease 2) (Memapsin-2)(Aspartyl protease 2) (Asp 2) (ASP2); (790:) Beta-secretase 2 precursor(Beta-site APP-cleaving enzyme 2) (Aspartyl protease 1) (Asp 1) (ASP1)(Membrane-associated aspartic protease 1) (Memapsin-1) (Down regionaspartic protease); (791:) beta-site APP cleaving enzyme [Homo sapiens];(792:) beta-site APP cleaving enzyme 1-432 [Homo sapiens]; (793:)beta-site APP cleaving enzyme 1-457 [Homo sapiens]; (794:) beta-site APPcleaving enzyme 1-476 [Homo sapiens]; (795:) beta-site APP cleavingenzyme isoform 1-127 [Homo sapiens]; (796:) beta-site APP cleavingenzyme type B [Homo sapiens]; (797:) beta-site APP cleaving enzyme typeC [Homo sapiens]; (798:) beta-site APP-cleaving enzyme [Homo sapiens];(799:) Beta-site APP-cleaving enzyme 1 [Homo sapiens]; (800:) beta-siteAPP-cleaving enzyme 1 isoform A preproprotein [Homo sapiens]; (801:)beta-site APP-cleaving enzyme 1 isoform B preproprotein [Homo sapiens];(802:) beta-site APP-cleaving enzyme 1 isoform C preproprotein [Homosapiens]; (803:) beta-site APP-cleaving enzyme 1 isoform D preproprotein[Homo sapiens]; (804:) Beta-site APP-cleaving enzyme 2 [Homo sapiens];(805:) beta-site APP-cleaving enzyme 2 isoform A preproprotein [Homosapiens]; (806:) beta-site APP-cleaving enzyme 2 isoform B preproprotein[Homo sapiens]; (807:) beta-site APP-cleaving enzyme 2 isoform Cpreproprotein [Homo sapiens]; (808:) beta-site APP-cleaving enzyme 2, EC3.4.23. [Homo sapiens]; (809:) beta-synuclein [Homo sapiens]; (810:)Beta-ureidopropionase (Beta-alanine synthase) (N-carbamoyl-beta-alanineamidohydrolase) (BUP-1); (811:) “Bifunctional 3′-phosphoadenosine5′-phosphosulfate synthetase 1(PAPS synthetase 1) (PAPSS1) (Sulfurylasekinase 1) (SK1) (SK 1)[Includes:) Sulfate adenylyltransferase (Sulfateadenylatetransferase) (SAT) (ATP-sulfurylase); Adenylyl-sulfate kinase(Adenylylsulfate 3′-phosphotransferase) (APS kinase)(Adenosine-5′-phosphosulfate 3′-phosphotransferase)(3′-phosphoadenosine-5′-phosphosulfate synthetase)].”; (812:)“Bifunctional 3′-phosphoadenosine 5′-phosphosulfate synthetase 2(PAPSsynthetase 2) (PAPSS 2) (Sulfurylase kinase 2) (SK2) (SK 2)[Includes:)Sulfate adenylyltransferase (Sulfate adenylatetransferase) (SAT)(ATP-sulfurylase); Adenylyl-sulfate kinase (Adenylylsulfate3′-phosphotransferase) (APS kinase) (Adenosine-5′-phosphosulfate3′-phosphotransferase) (3′-phosphoadenosine-5′-phosphosulfatesynthetase)].”; (813:) bifunctional ATP sulfurylase/adenosine5′-phosphosulfate kinase [Homo sapiens]; (814:) “Bifunctional coenzyme Asynthase (CoA synthase) (NBP) (POV-2)[Includes:) Phosphopantetheineadenylyltransferase (Pantetheine-phosphate adenylyltransferase) (PPAT)(Dephospho-CoA pyrophosphorylase); Dephospho-CoA kinase (DPCK)(Dephospho coenzyme A kinase) (DPCOAK)].”; (815:) “Bifunctional heparansulfate N-deacetylase/N-sulfotransferase 1(GlucosaminylN-deacetylase/N-sulfotransferase 1) (NDST-1) ([Heparansulfate]-glucosamine N-sulfotransferase 1) (HSNST1) (N-heparan sulfatesulfotransferase 1) (N-HSST 1) [Includes:Heparan sulfate N-deacetylase1; Heparan sulfate N-sulfotransferase 1].”; (816:) “Bifunctional heparansulfate N-deacetylase/N-sulfotransferase 2(GlucosaminylN-deacetylase/N-sulfotransferase 2) (NDST-2) (N-heparan sulfatesulfotransferase 2) (N-HSST 2) [Includes:Heparan sulfate N-deacetylase2; Heparan sulfate N-sulfotransferase 2].”; (817:) “Bifunctional heparansulfate N-deacetylase/N-sulfotransferase 3(GlucosaminylN-deacetylase/N-sulfotransferase 3) (NDST-3) (hNDST-3) (N-heparansulfate sulfotransferase 3) (N-HSST 3)[Includes:) Heparan sulfateN-deacetylase 3; Heparan sulfate N-sulfotransferase 3].”; (818:)“Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase4(Glucosaminyl N-deacetylase/N-sulfotransferase 4) (NDST-4) (N-heparansulfate sulfotransferase 4) (N-HSST 4) [Includes:Heparan sulfateN-deacetylase 4; Heparan sulfate N-sulfotransferase 4].”; (819:)“Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase,mitochondrial precursor [Includes: NAD-dependentmethylenetetrahydrofolate dehydrogenase; Methenyltetrahydrofolatecyclohydrolase].”; (820:) bifunctional phosphopantetheine adenylyltransferase/dephospho CoA kinase [Homo sapiens]; (821:) “Bifunctionalprotein NCOAT (Nuclear cytoplasmic O-GlcNAcase and acetyltransferase)(Meningioma-expressed antigen 5) [Includes:Beta-hexosaminidase(N-acetyl-beta-glucosaminidase) (Beta-N-acetylhexosaminidase)(Hexosaminidase C) (N-acetyl-beta-D-glucosaminidase) (O-GlcNAcase);Histoneacetyltransferase (HAT)].”; (822:) “BifunctionalUDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase(UDP-GlcNAc-2-epimerase/ManAc kinase) [Includes:UDP-N-acetylglucosamine2-epimerase (Uridine diphosphate-N-acetylglucosamine-2-epimerase)(UDP-GlcNAc-2-epimerase); N-acetylmannosamine kinase (ManAckinase)].”;(823:) bile acid beta-glucosidase [Homo sapiens]; (824:) bile acid CoA:)Amino acid N-acyltransferase; (825:) Bile acid CoA:amino acidN-acyltransferase (BAT) (BACAT) (Glycine N-choloyltransferase)(Long-chain fatty-acyl-CoA hydrolase); (826:) bile acid Coenzyme A:)amino acid N-acyltransferase [Homo sapiens]; (827:) Bile acid receptor(Farnesoid X-activated receptor) (Farnesol receptor HRR-1) (Retinoid Xreceptor-interacting protein 14) (RXR-interacting protein 14); (828:)Bile acyl-CoA synthetase (BACS) (Bile acid CoA ligase) (BA-CoA ligase)(BAL) (Cholate-CoA ligase) (Very long-chain acyl-CoA synthetase homolog2) (VLCSH2) (VLCS-H2) (Very long chain acyl-CoA synthetase-relatedprotein) (VLACS-related) (VLACSR) (Fatty-acid-coenzyme A ligase, verylong-chain 3) (Fatty acid transport protein 5) (FATP-5) (Solute carrierfamily 27 member 5); (829:) Bile salt sulfotransferase (HydroxysteroidSulfotransferase) (HST) (Dehydroepiandrosterone sulfotransferase)(DHEA-ST) (ST2) (ST2A3); (830:) Bile salt-activated lipase precursor(BAL) (Bile salt-stimulated lipase) (BSSL) (Carboxyl ester lipase)(Sterol esterase) (Cholesterol esterase) (Pancreatic lysophospholipase);(831:) biliverdin reductase B (flavin reductase (NADPH)) [Homo sapiens];(832:) biphenyl hydrolase-like [Homo sapiens]; (833:)Bis(5′-adenosyl)-triphosphatase (Diadenosine-5′,5″-P1,P3-triphosphatehydrolase) (Dinucleosidetriphosphatase) (AP3A hydrolase) (AP3AASE)(Fragile histidine triad protein); (834:) BK158_(—)1(OTTHUMP00000040718) variant [Homo sapiens]; (835:) BK158_(—)1 [Homosapiens]; (836:) bleomycin hydrolase [Homo sapiens]; (837:)Blue-sensitive opsin (BOP) (Blue cone photoreceptor pigment); (838:)Bombesin receptor subtype-3 (BRS-3); (839:) bone morphogenetic protein 1isoform 1, precursor [Homo sapiens]; (840:) bone morphogenetic protein 1isoform 2, precursor [Homo sapiens]; (841:) bone morphogenetic protein 1isoform 3, precursor [Homo sapiens]; (842:) Bone morphogenetic protein 1precursor (BMP-1) (Procollagen C-proteinase) (PCP) (Mammalian tolloidprotein) (mTld); (843:) Bone morphogenetic protein receptor type IAprecursor (Serine/threonine-protein kinase receptor R5) (SKR5) (Activinreceptor-like kinase 3) (ALK-3) (CD292 antigen); (844:) Bonemorphogenetic protein receptor type IB precursor (CDw293antigen); (845:)Bone morphogenetic protein receptor type-2 precursor (Bone morphogeneticprotein receptor type II) (BMP type II receptor) (BMPR-II); (846:)bradykinin receptor B1 [Homo sapiens]; (847:) bradykinin receptor B2[Homo sapiens]; (848:) brain creatine kinase [Homo sapiens]; (849:)brain glycogen phosphorylase [Homo sapiens]; (850:) brain-derivedneurotrophic factor isoform a preproprotein [Homo sapiens]; (851:)brain-derived neurotrophic factor isoform b preproprotein [Homosapiens]; (852:) brain-derived neurotrophic factor isoform cpreproprotein [Homo sapiens]; (853:) Brain-specific angiogenesisinhibitor 1 precursor; (854:) Brain-specific angiogenesis inhibitor 2precursor; (855:) Brain-specific angiogenesis inhibitor 3 precursor;(856:) branched chain acyltransferase precursor; (857:) branched chainaminotransferase 1, cytosolic [Homo sapiens]; (858:) branched chainaminotransferase 2, mitochondrial [Homo sapiens]; (859:) branched chainketo acid dehydrogenase E1, alpha polypeptide [Homo sapiens]; (860:)branching-enzyme interacting dual-specificity protein phosphatase BEDP[Homo sapiens]; (861:) Breast cancer type 1 susceptibility protein (RINGfinger protein53); (862:) Brefeldin A-inhibited guaninenucleotide-exchange protein 1(Brefeldin A-inhibited GEP 1) (p200ARF-GEP1) (p200 ARF guanine nucleotide exchange factor); (863:)Brefeldin A-inhibited guanine nucleotide-exchange protein 2(BrefeldinA-inhibited GEP 2); (864:) bubblegum related protein [Homo sapiens];(865:) butyrylcholinesterase precursor [Homo sapiens]; (866:)C->U-editing enzyme APOBEC-1 (Apolipoprotein B mRNA-editing enzyme1)(HEPR); (867:) C1 esterase inhibitor [Homo sapiens]; (868:) C10orf129protein [Homo sapiens]; (869:) C1GALT1-specific chaperone 1 [Homosapiens]; (870:) C1-tetrahydrofolate synthase [Homo sapiens]; (871:)“C-1-tetrahydrofolate synthase, cytoplasmic (C1-THF synthase)[Includes:)Methylenetetrahydrofolate dehydrogenase; Methenyltetrahydrofolatecyclohydrolase; Formyltetrahydrofolatesynthetase].”; (872:) C3aanaphylatoxin chemotactic receptor (C3a-R) (C3AR); (873:) C5aanaphylatoxin chemotactic receptor (C5a-R) (C5aR) (CD88antigen); (874:)C5a anaphylatoxin chemotactic receptor C5L2 (G-protein coupled receptor77); (875:) C9orf3 protein [Homo sapiens]; (876:) C9orf95 protein [Homosapiens]; (877:) Ca2+/calmodulin-dependent protein kinase (EC 2.7.1.123)II gamma chain, splice form B—human; (878:) Ca2+/calmodulin-dependentprotein kinase kinase beta-3 [Homo sapiens]; (879:) CAD protein [Homosapiens]; (880:) cadherin 1, type 1 preproprotein [Homo sapiens]; (881:)Cadherin EGF LAG seven-pass G-type receptor 1 precursor (Flamingohomolog 2) (hFmi2); (882:) Cadherin EGF LAG seven-pass G-type receptor 2precursor (Epidermal growth factor-like 2) (Multiple epidermal growthfactor-like domains 3) (Flamingo 1); (883:) Cadherin EGF LAG seven-passG-type receptor 3 precursor (Flamingo homolog 1) (hFmi1) (Multipleepidermal growth factor-like domains2) (Epidermal growth factor-like 1);(884:) Calcitonin gene-related peptide type 1 receptor precursor (CGRPtype 1 receptor) (Calcitonin receptor-like receptor); (885:) calcitoningene-related peptide-receptor component protein isoform a [Homosapiens]; (886:) calcitonin gene-related peptide-receptor componentprotein isoform b [Homo sapiens]; (887:) calcitonin gene-relatedpeptide-receptor component protein isoform c [Homo sapiens]; (888:)Calcitonin receptor precursor (CT-R); (889:) calcium activatednucleotidase 1 [Homo sapiens]; (890:) calcium receptor (clonephPCaR-4.0)—human; (891:) calcium receptor (clone phPCaR-5.2)—human;(892:) Calcium/calmodulin-dependent 3′,5′-cyclic nucleotidephosphodiesterase 1A (Cam-PDE1A) (61 kDa Cam-PDE) (hCam-1); (893:)Calcium/calmodulin-dependent 3′,5′-cyclic nucleotide phosphodiesterase1B (Cam-PDE 1B) (63 kDa Cam-PDE); (894:) Calcium/calmodulin-dependent3′,5′-cyclic nucleotide phosphodiesterase 1C (Cam-PDE 1C) (hCam-3);(895:) calcium/calmodulin-dependent protein kinase I [Homo sapiens];(896:) calcium/calmodulin-dependent protein kinase II delta isoform 1[Homo sapiens]; (897:) calcium/calmodulin-dependent protein kinase IIdelta isoform 2 [Homo sapiens]; (898:) calcium/calmodulin-dependentprotein kinase II delta isoform 3 [Homo sapiens]; (899:)calcium/calmodulin-dependent protein kinase II gamma isoform 1 [Homosapiens]; (900:) calcium/calmodulin-dependent protein kinase II gammaisoform 2 [Homo sapiens]; (901:) calcium/calmodulin-dependent proteinkinase II gamma isoform 3 [Homo sapiens]; (902:)calcium/calmodulin-dependent protein kinase II gamma isoform 4 [Homosapiens]; (903:) calcium/calmodulin-dependent protein kinase II gammaisoform 5 [Homo sapiens]; (904:) calcium/calmodulin-dependent proteinkinase II gamma isoform 6 [Homo sapiens]; (905:)calcium/calmodulin-dependent protein kinase IIA isoform 1 [Homosapiens]; (906:) calcium/calmodulin-dependent protein kinase IIA isoform2 [Homo sapiens]; (907:) calcium/calmodulin-dependent protein kinase IIBisoform 1 [Homo sapiens]; (908:) calcium/calmodulin-dependent proteinkinase IIB isoform 2 [Homo sapiens]; (909:) calcium/calmodulin-dependentprotein kinase IIB isoform 3 [Homo sapiens]; (910:)calcium/calmodulin-dependent protein kinase IIB isoform 4 [Homosapiens]; (911:) calcium/calmodulin-dependent protein kinase IIB isoform5 [Homo sapiens]; (912:) calcium/calmodulin-dependent protein kinase IIBisoform 6 [Homo sapiens]; (913:) calcium/calmodulin-dependent proteinkinase IIB isoform 7 [Homo sapiens]; (914:) calcium/calmodulin-dependentprotein kinase IIB isoform 8 [Homo sapiens]; (915:)calcium/calmodulin-dependent protein kinase IV [Homo sapiens]; (916:)Calcium/calmodulin-dependent protein kinase kinase1(Calcium/calmodulin-dependent protein kinase kinase alpha) (CaM-kinasekinase alpha) (CaM-KK alpha) (CaMKK alpha) (CaMKK 1) (CaM-kinase IVkinase); (917:) Calcium/calmodulin-dependent protein kinase kinase2(Calcium/calmodulin-dependent protein kinase kinase beta) (CaM-kinasekinase beta) (CaM-KK beta) (CaMKK beta); (918:)Calcium/calmodulin-dependent protein kinase type 1 (CaM kinase I)(CaM-KI) (CaM kinase 1 alpha) (CaMKI-alpha); (919:)Calcium/calmodulin-dependent protein kinase type 1B (CaM kinase IB) (CaMkinase 1 beta) (CaMKI-beta) (CaM-KI beta) (Pregnancyup-regulatednon-ubiquitously expressed CaM kinase); (920:)Calcium/calmodulin-dependent protein kinase type 1D (CaM kinase ID) (CaMkinase I delta) (CaMKI-delta) (CaM-KI delta) (CaMKI delta) (Camk1D)(CamKI-like protein kinase) (CKLiK); (921:) Calcium/calmodulin-dependentprotein kinase type 1G (CaM kinase IG) (CaM kinase I gamma) (CaMKIgamma) (CaMKI-gamma) (CaM-KI gamma) (CaMKIG) (CaMK-like CREB kinase III)(CLICK III); (922:) Calcium/calmodulin-dependent protein kinase type IIalpha chain (CaM-kinase II alpha chain) (CaM kinase II alpha subunit)(CaMK-II subunit alpha); (923:) Calcium/calmodulin-dependent proteinkinase type II beta chain (CaM-kinase II beta chain) (CaM kinase IIsubunit beta) (CaMK-II subunit beta); (924:)Calcium/calmodulin-dependent protein kinase type II delta chain(CaM-kinase II delta chain) (CaM kinase II subunit delta) (CaMK-IIsubunit delta); (925:) Calcium/calmodulin-dependent protein kinase typeII gamma chain (CaM-kinase II gamma chain) (CaM kinase II gamma subunit)(CaMK-II subunit gamma); (926:) Calcium/calmodulin-dependent proteinkinase type IV (CAM kinase-GR) (CaMK IV); (927:) Calcium-dependentphospholipase A2 precursor (Phosphatidylcholine-2-acylhydrolase)(PLA2-10) (Group V phospholipase A2); (928:) calcium-independentphospholipase A2 [Homo sapiens]; (929:) calcium-sensing receptor [Homosapiens]; (930:) calcium-transporting ATPase 2C1 isoform 1a [Homosapiens]; (931:) calcium-transporting ATPase 2C1 isoform 1b [Homosapiens]; (932:) calcium-transporting ATPase 2C1 isoform 1c [Homosapiens]; (933:) calcium-transporting ATPase 2C1 isoform 1d [Homosapiens]; (934:) Calcium-transporting ATPase type 2C member I (ATPase2C1) (ATP-dependent Ca(2+) pump PMR1); (935:) Calmodulin (Vertebrate);(936:) calmodulin-like skin protein [Homo sapiens]; (937:) calnexinprecursor [Homo sapiens]; (938:) calpain [Homo sapiens]; (939:) calpain1, large subunit [Homo sapiens]; (940:) calpain 2, large subunit [Homosapiens]; (941:) calpain 3 isoform a [Homo sapiens]; (942:) calpain 3isoform b [Homo sapiens]; (943:) calpain 3 isoform c [Homo sapiens];(944:) calpain 3 isoform d [Homo sapiens]; (945:) calpain 3 isoform e[Homo sapiens]; (946:) calpain 3 isoform f [Homo sapiens]; (947:)calpain 3 isoform g [Homo sapiens]; (948:) calpain 3 isoform h [Homosapiens]; (949:) Calpain-1 catalytic subunit (Calpain-1 large subunit)(Calcium-activated neutral proteinase 1) (CANP1) (Calpain mu-type)(muCANP) (Micromolar-calpain); (950:) Calpain-2 catalytic subunitprecursor (Calpain-2 large subunit) (Calcium-activated neutralproteinase 2) (CANP 2) (Calpain M-type) (M-calpain) (Millimolar-calpain)(Calpain large polypeptide L2); (951:) Calpain-3 (Calpain L3) (Calpainp94) (Calcium-activated neutral proteinase 3) (CANP 3) (Muscle-specificcalcium-activated neutral protease 3) (nCL-1); (952:)C-alpha-formyglycine-generating enzyme [Homo sapiens]; (953:) cAMP andcAMP-inhibited cGMP 3′,5′-cyclic phosphodiesterase 10A; (954:) cAMPresponsive element binding protein 3 [Homo sapiens]; (955:)cAMP-dependent protein kinase catalytic subunit alpha isoform 1 [Homosapiens]; (956:) cAMP-dependent protein kinase catalytic subunit alphaisoform 2 [Homo sapiens]; (957:) cAMP-dependent protein kinase inhibitoralpha (PKI-alpha) (cAMP-dependent protein kinase inhibitor, muscle/brainisoform); (958:) cAMP-dependent protein kinase inhibitor beta(PKI-beta); (959:) cAMP-dependent protein kinase inhibitor gamma(PKI-gamma); (960:) cAMP-dependent protein kinase type I-alpharegulatory subunit (Tissue-specific extinguisher 1) (TSE1); (961:)cAMP-dependent protein kinase type 1-beta regulatory subunit; (962:)cAMP-dependent protein kinase type 11-alpha regulatory subunit; (963:)cAMP-dependent protein kinase type II-beta regulatory subunit; (964:)cAMP-dependent protein kinase, alpha-catalytic subunit (PKAC-alpha);(965:) cAMP-dependent protein kinase, beta-catalytic subunit (PKAC-beta); (966:) cAMP-dependent protein kinase, gamma-catalytic subunit(PKAC-gamma); (967:) cAMP-specific 3′,5′-cyclic phosphodiesterase 4A(DPDE2) (PDE46); (968:) cAMP-specific 3′,5′-cyclic phosphodiesterase 4B(DPDE4) (PDE32); (969:) cAMP-specific 3′,5′-cyclic phosphodiesterase 4C(DPDE1) (PDE21); (970:) cAMP-specific 3′,5′-cyclic phosphodiesterase 4D(DPDE3) (PDE43); (971:) cAMP-specific 3′,5′-cyclic phosphodiesterase 7B;(972:) cAMP-specific phosphodiesterase 4D [Homo sapiens]; (973:)Cannabinoid receptor 1 (CB1) (CB-R) (CANN6); (974:) Cannabinoid receptor2 (CB2) (CB-2) (CX5); (975:) CAP10-like 46 kDa protein precursor(Myelodysplastic syndromes relative protein); (976:) capping enzyme 1[Homo sapiens]; (977:) capping enzyme IA [Homo sapiens]; (978:) cappingenzyme 1B [Homo sapiens]; (979:) Carbamoyl-phosphate synthase [ammonia],mitochondrial precursor (Carbamoyl-phosphate synthetase 1) (CPSase I);(980:) carbamoyl-phosphate synthetase 1, mitochondrial [Homo sapiens];(981:) Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, anddihydroorotase [Homo sapiens]; (982:) carbamoylphosphate synthetase2/aspartate transcarbamylase/dihydroorotase [Homo sapiens]; (983:)carbohydrate (N-acetylglucosamine 6-0) sulfotransferase 6 [Homosapiens]; (984:) carbohydrate (N-acetylglucosamine 6-0) sulfotransferase7 [Homo sapiens]; (985:) carbohydrate (N-acetylglucosamine-6-0)sulfotransferase 2 [Homo sapiens]; (986:) Carbohydrate sulfotransferase10 (HNK-1 sulfotransferase) (HNK1ST) (HNK-1ST) (huHNK-1ST); (987:)Carbohydrate sulfotransferase 11 (Chondroitin 4-O-sulfotransferase 1)(Chondroitin 4-sulfotransferase 1) (C4ST) (C4ST-1) (C4ST); (988:)Carbohydrate sulfotransferase 12 (Chondroitin 4-O-sulfotransferase 2)(Chondroitin 4-sulfotransferase 2) (C4ST2) (C4ST-2) (SulfotransferaseHlo); (989:) Carbohydrate sulfotransferase 13 (Chondroitin4-O-sulfotransferase 3) (Chondroitin 4-sulfotransferase 3) (C4ST3)(C4ST-3); (990:) Carbohydrate sulfotransferase 2(N-acetylglucosamine-6-O-sulfotransferase 1) (GlcNAc6ST-1) (Gn6ST)(Galactose/N-acetylglucosamine/N-acetylglucosamine-6-O-sulfotransferase2) (GST-2); (991:) Carbohydrate sulfotransferase 3 (Chondroitin6-sulfotransferase) (Chondroitin 6-O-sulfotransferase 1) (C6ST-1) (C6ST)(Galactose/N-acetylglucosamine/N-acetylglucosamine-6-O-sulfotransferase0) (GST-0); (992:) Carbohydrate sulfotransferase 4(N-acetylglucosamine-6-O-sulfotransferase 2) (GlcNAc6ST-2) (Highendothelial cells N-acetylglucosamine 6-O-sulfotransferase)(HEC-GlcNAc6ST) (L-selectin ligand sulfotransferase) (LSST)(Galactose/N-acetylglucosamine/N-acetylglucosamine-6-O-sulfotransferase3) (GST-3); (993:) Carbohydrate sulfotransferase 7 (Chondroitin6-sulfotransferase 2) (C6ST-2) (N-acetylglucosamine6-O-sulfotransferase 1) (GlcNAc6ST-4)(Galactose/N-acetylglucosamine/N-acetylglucosamine-6-O-sulfotransferase5) (GST-5); (994:) Carbohydrate sulfotransferase8(N-acetylgalactosamine-4-O-sulfotransferase 1)(GalNAc-4-O-sulfotransferase 1) (GalNAc-4-ST1) (GalNAc4ST-1); (995:)Carbohydrate sulfotransferase9(N-acetylgalactosamine-4-O-sulfotransferase 2)(GalNAc-4-O-sulfotransferase 2) (GalNAc-4-ST2); (996:) Carbohydratesulfotransferase D4ST1 (Dermatan 4-sulfotransferase 1) (D4ST-1) (hD4ST);(997:) Carbonic anhydrase 12 precursor (Carbonic anhydrase XII)(Carbonate dehydratase XII) (CA-XII) (Tumor antigen HOM-RCC-3.1.3);(998:) Carbonic anhydrase 4 precursor (Carbonic anhydrase IV) (Carbonatedehydratase IV) (CA-IV); (999:) Carbonic Anhydrase I (E.C.4.2.1.1)Complexed With Bicarbonate; (1000:) carbonic anhydrase I [Homo sapiens];(1001:) carbonic anhydrase 11 [Homo sapiens]; (1002:) carbonic anhydraseIV precursor [Homo sapiens]; (1003:) carbonic anhydrase IX precursor[Homo sapiens]; (1004:) carbonic anhydrase VIII [Homo sapiens]; (1005:)carbonyl reductase 1 [Homo sapiens]; (1006:) carbonyl reductase 3 [Homosapiens]; (1007:) carboxyl ester lipase precursor [Homo sapiens];(1008:) carboxylesterase 1 isoform a precursor [Homo sapiens]; (1009:)carboxylesterase 1 isoform b precursor [Homo sapiens]; (1010:)carboxylesterase 1 isoform c precursor [Homo sapiens]; (1011:)carboxylesterase 2 isoform 1 [Homo sapiens]; (1012:) carboxylesterase 2isoform 2 [Homo sapiens]; (1013:) carboxylesterase; (1014:)carboxypeptidase A2 (pancreatic) [Homo sapiens]; (1015:)carboxypeptidase A4 preproprotein [Homo sapiens]; (1016:)carboxypeptidase A5 [Homo sapiens]; (1017:) carboxypeptidase B precursor[Homo sapiens]; (1018:) Carboxypeptidase D precursor(Metallocarboxypeptidase D) (gp180); (1019:) carboxypeptidase Eprecursor [Homo sapiens]; (1020:) Carboxypeptidase M precursor (CPM);(1021:) carboxypeptidase N, polypeptide 1, 50 kD precursor [Homosapiens]; (1022:) carboxypeptidase Z isoform 1 [Homo sapiens]; (1023:)carboxypeptidase Z isoform 2 precursor [Homo sapiens]; (1024:)carboxypeptidase Z isoform 3 [Homo sapiens]; (1025:) Carboxypeptidase Zprecursor (CPZ); (1026:) carnitine acetyltransferase isoform 1 precursor[Homo sapiens]; (1027:) carnitine acetyltransferase isoform 2 [Homosapiens]; (1028:) carnitine acetyltransferase isoform 3 precursor [Homosapiens]; (1029:) Carnitine O-acetyltransferase (Carnitine acetylase)(CAT) (Carnitine acetyltransferase) (CrAT); (1030:) carnitineO-octanoyltransferase [Homo sapiens]; (1031:) CarnitineO-palmitoyltransferase I, liver isoform (CPT I) (CPTI-L) (Carnitinepalmitoyltransferase 1A); (1032:) carnitine palmitoyltransferase 1Aisoform 1 [Homo sapiens]; (1033:) carnitine palmitoyltransferase 1Aisoform 2 [Homo sapiens]; (1034:) carnitine palmitoyltransferase 1βisoform a [Homo sapiens]; (1035:) carnitine palmitoyltransferase 1βisoform b [Homo sapiens]; (1036:) “Cartilage intermediate layer protein1 precursor (CILP-1) (Cartilage intermediate-layer protein) [Contains:)Cartilage intermediate layer protein 1 C1; Cartilage intermediate layerprotein 1 C2].”; (1037:) Cas-Br-M (murine) ecotropic retroviraltransforming sequence [Homo sapiens]; (1038:) casein alpha s1 isoform 1[Homo sapiens]; (1039:) casein alpha s1 isoform 2 [Homo sapiens];(1040:) casein beta [Homo sapiens]; (1041:) casein kinase 1, gamma 1[Homo sapiens]; (1042:) casein kinase 1, gamma 1 isoform L [Homosapiens]; (1043:) casein kinase 2, alpha prime polypeptide [Homosapiens]; (1044:) casein kinase 2, beta polypeptide [Homo sapiens];(1045:) Casein kinase I isoform delta (CKI-delta) (CKId); (1046:) caseinkinase II alpha 1 subunit isoform a [Homo sapiens]; (1047:) caseinkinase II alpha 1 subunit isoform b [Homo sapiens]; (1048:) CASH alphaprotein [Homo sapiens]; (1049:) CASP1 protein [Homo sapiens]; (1050:)CASP10 protein [Homo sapiens]; (1051:) CASP12P1 [Homo sapiens]; (1052:)CASP2 [Homo sapiens]; (1053:) CASP8 and FADD-like apoptosis regulator[Homo sapiens]; (1054:) “CASP8 and FADD-like apoptosis regulatorprecursor (Cellular FLICE-like inhibitory protein) (c-FLIP)(Caspase-eight-related protein) (Casper) (Caspase-like apoptosisregulatory protein) (CLARP) (MACH-related inducer of toxicity) (MRIT)(Caspase homolog) (CASH) (Inhibitor of FLICE) (I-FLICE) (FADD-likeantiapoptotic molecule 1) (FLAME-1) (Usurpin) [Contains:) CASP8 andFADD-like apoptosis regulator subunit p43; CASP8 and FADD-like apoptosisregulator subunit p12].”; (1055:) CASP8 protein [Homo sapiens]; (1056:)caspase 1 isoform alpha precursor [Homo sapiens]; (1057:) caspase 1isoform alpha precursor variant [Homo sapiens]; (1058:) caspase 1isoform beta precursor [Homo sapiens]; (1059:) caspase 1 isoform delta[Homo sapiens]; (1060:) caspase 1 isoform epsilon [Homo sapiens];(1061:) caspase 1 isoform gamma precursor [Homo sapiens]; (1062:)Caspase 1, apoptosis-related cysteine peptidase (interleukin 1,beta,convertase) [Homo sapiens]; (1063:) caspase 10 [Homo sapiens]; (1064:)caspase 10 isoform a preproprotein [Homo sapiens]; (1065:) caspase 10isoform b preproprotein [Homo sapiens]; (1066:) caspase 10 isoform dpreproprotein [Homo sapiens]; (1067:) caspase 10, apoptosis-relatedcysteine peptidase [Homo sapiens]; (1068:) caspase 14 precursor [Homosapiens]; (1069:) Caspase 14, apoptosis-related cysteine peptidase [Homosapiens]; (1070:) caspase 2 isoform 1 preproprotein [Homo sapiens];(1071:) caspase 2 isoform 2 precursor variant [Homo sapiens]; (1072:)caspase 2 isoform 3 [Homo sapiens]; (1073:) Caspase 2, apoptosis-relatedcysteine peptidase (neural precursor cell expressed, developmentallydown-regulated 2) [Homo sapiens]; (1074:) caspase 2, apoptosis-relatedcysteine protease (neural precursor cell expressed, developmentallydown-regulated 2) [Homo sapiens]; (1075:) caspase 3 preproprotein [Homosapiens]; (1076:) Caspase 3, apoptosis-related cysteine peptidase [Homosapiens]; (1077:) caspase 3, apoptosis-related cysteine protease [Homosapiens]; (1078:) caspase 4 isoform alpha precursor [Homo sapiens];(1079:) caspase 4 isoform delta [Homo sapiens]; (1080:) caspase 4isoform gamma precursor [Homo sapiens]; (1081:) Caspase 4,apoptosis-related cysteine peptidase [Homo sapiens]; (1082:) caspase 5precursor [Homo sapiens]; (1083:) Caspase 5, apoptosis-related cysteinepeptidase [Homo sapiens]; (1084:) caspase 6 isoform alpha preproprotein[Homo sapiens]; (1085:) caspase 6 isoform beta [Homo sapiens]; (1086:)Caspase 6, apoptosis-related cysteine peptidase [Homo sapiens]; (1087:)caspase 6, apoptosis-related cysteine protease [Homo sapiens]; (1088:)caspase 7 isoform alpha [Homo sapiens]; (1089:) caspase 7 isoform alphaprecursor [Homo sapiens]; (1090:) caspase 7 isoform beta [Homo sapiens];(1091:) caspase 7 isoform delta [Homo sapiens]; (1092:) Caspase 7,apoptosis-related cysteine peptidase [Homo sapiens]; (1093:) caspase 7,apoptosis-related cysteine protease [Homo sapiens]; (1094:) caspase 8isoform A [Homo sapiens]; (1095:) caspase 8 isoform B precursor [Homosapiens]; (1096:) caspase 8 isoform C [Homo sapiens]; (1097:) caspase 8isoform E [Homo sapiens]; (1098:) caspase 8, apoptosis-related cysteinepeptidase [Homo sapiens]; (1099:j caspase 9 isoform alpha preproprotein[Homo sapiens]; (1100:) caspase 9 isoform alpha preproprotein variant[Homo sapiens]; (1101:) caspase 9 isoform beta preproprotein [Homosapiens]; (1102:) caspase 9 short isoform [Homo sapiens]; (1103:)Caspase 9, apoptosis-related cysteine peptidase [Homo sapiens]; (1104:)caspase 9, apoptosis-related cysteine protease [Homo sapiens]; (1105:)caspase-1 dominant-negative inhibitor pseudo-ICE isoform 1 [Homosapiens]; (1106:) caspase-1 dominant-negative inhibitor pseudo-ICEisoform 2 [Homo sapiens]; (1107:) caspase-1 isoform zeta precursor [Homosapiens]; (1108:) “Caspase-1 precursor (CASP-1) (Interleukin-1 betaconvertase) (IL-1BC) (IL-1 beta-converting enzyme) (ICE) (Interleukin-1beta-converting enzyme) (p45) [Contains:) Caspase-1 p20 subunit;Caspase-1 p10 subunit].”; (1109:) “Caspase-10 precursor (CASP-10)(ICE-like apoptotic protease 4) (Apoptotic protease Mch-4)(FAS-associated death domain protein interleukin-1B-converting enzyme 2)(FLICE2) [Contains:) Caspase-10 subunit p23/17; Caspase-10 subunitp12].”; (1110:) caspase-10/d [Homo sapiens]; (1111:) caspase-10a [Homosapiens]; (1112:) caspase-10b [Homo sapiens]; (1113:) “Caspase-14precursor (CASP-14) [Contains:) Caspase-14 subunit 1; Caspase-14 subunit2].”; (1114:) “Caspase-2 precursor (CASP-2) (ICH-1 protease) (ICH-1L/1S)[Contains:) Caspase-2 subunit p18; Caspase-2 subunit p13;Caspase-2subunit p12].”; (1115:) caspase-3 [Homo sapiens]; (1116:)“Caspase-3 precursor (CASP-3) (Apopain) (Cysteine protease CPP32) (Yamaprotein) (CPP-32) (SREBP cleavage activity 1) (SCA-1)[Contains:)Caspase-3 p17 subunit; Caspase-3 p12 subunit].”; (1117:) “Caspase-4precursor (CASP-4) (ICH-2 protease) (TX protease) (ICE(rel)-II)[Contains:) Caspase-4 subunit 1; Caspase-4 subunit 2].”; (1118:)“Caspase-5 precursor (CASP-5) (ICH-3 protease) (TY protease)(ICE(rel)-III) [Contains:) Caspase-5 subunit p20; Caspase-5 subunitp10].”; (1119:) caspase-5/b [Homo sapiens]; (1120:) caspase-5/f [Homosapiens]; (1121:) “Caspase-6 precursor (CASP-6) (Apoptotic proteaseMch-2) [Contains:Caspase-6 subunit p18; Caspase-6 subunit p11].”;(1122:) “Caspase-7 precursor (CASP-7) (ICE-like apoptotic protease 3)(ICE-LAP3) (Apoptotic protease Mch-3) (CMH-1) [Contains:) Caspase-7subunit p20; Caspase-7 subunit p11].”; (1123:) caspase-8 [Homo sapiens];(1124:) “Caspase-8 precursor (CASP-8) (ICE-like apoptotic protease 5)(MORT1-associated CED-3 homolog) (MACH) (FADD-homologous ICE/CED-3-likeprotease) (FADD-like ICE) (FLICE) (Apoptotic cysteine protease)(Apoptotic protease Mch-5) (CAP4) [Contains:Caspase-8 subunit p18;Caspase-8 subunit p10].”; (1125:) caspase-8L [Homo sapiens]; (1126:)Caspase-9 [Homo sapiens]; (1127:) caspase-9 beta [Homo sapiens]; (1128:)“Caspase-9 precursor (CASP-9) (ICE-like apoptotic protease 6) (ICE-LAP6)(Apoptotic protease Mch-6) (Apoptotic protease-activating factor 3)(APAF-3) [Contains:) Caspase-9 subunit p35; Caspase-9 subunit p10].”;(1129:) caspase-9S precursor [Homo sapiens]; (1130:) caspase-likeapoptosis regulatory protein [Homo sapiens]; (1131:) Casper [Homosapiens]; (1132:) catalase [Homo sapiens]; (1133:) CatecholO-methyltransferase; (1134:) catechol-O-methyltransferase isoformMB-COMT [Homo sapiens]; (1135:) catechol-O-methyltransferase isoformS-COMT [Homo sapiens]; (1136:) catenin (cadherin-associated protein),beta 1, 88 kDa [Homo sapiens]; (1137:) cathepsin B preproprotein [Homosapiens]; (1138:) cathepsin C isoform a preproprotein [Homo sapiens];(1139:) cathepsin C isoform b precursor [Homo sapiens]; (1140:)cathepsin D preproprotein [Homo sapiens]; (1141:) Cathepsin E precursor;(1142:) Cathepsin F precursor (CATSF); (1143:) cathepsin G preproprotein[Homo sapiens]; (1144:) cathepsin H isoform a preproprotein [Homosapiens]; (1145:) cathepsin H isoform b precursor [Homo sapiens];(1146:) cathepsin K preproprotein [Homo sapiens]; (1147:) cathepsin Lpreproprotein [Homo sapiens]; (1148:) Cathepsin L2 precursor (CathepsinV) (Cathepsin U); (1149:) cathepsin O [Homo sapiens]; (1150:) CathepsinO precursor; (1151:) cathepsin O preproprotein [Homo sapiens]; (1152:)cathepsin S [Homo sapiens]; (1153:) cathepsin S preproprotein [Homosapiens]; (1154:) Cation-dependent mannose-6-phosphate receptorprecursor (CD Man-6-Preceptor) (CD-MPR) (46 kDa mannose 6-phosphatereceptor) (MPR 46); (1155:) cation-dependent mannose-6-phosphatereceptor precursor [Homo sapiens]; (1156:) Cation-independentmannose-6-phosphate receptor precursor (CIMan-6-P receptor) (CI-MPR)(M6PR) (Insulin-like growth factor 2receptor) (Insulin-like growthfactor II receptor) (IGF-II receptor) (M6P/IGF2 receptor) (M6P/IGF2R)(300 kDa mannose6-phosphate receptor) (MPR 300) (MPR300) (CD222antigen); (1157:) caveolin 1 [Homo sapiens]; (1158:) CBS protein [Homosapiens]; (1159:) C-C chemokine receptor type 11 (C-C CKR-1) (CC-CKR-1)(CCR-1) (CCR1) (Macrophage inflammatory protein 1-alpha receptor)(MIP-1alpha-R) (RANTES-R) (HM145) (LD78 receptor) (CD191 antigen);(1160:) C-C chemokine receptor type 10 (C-C CKR-10) (CC-CKR-10) (CCR-10)(G-protein coupled receptor 2); (1161:) C-C chemokine receptor type II(C-C CKR-1) (CC-CKR-11) (CCR-11) (CC chemokine receptor-like 1) (CCRL1)(CCX CKR); (1162:) C-C chemokine receptor type 2 (C-C CKR-2) (CC-CKR-2)(CCR-2) (CCR2) (Monocyte chemoattractant protein 1 receptor) (MCP-1-R)(CD192antigen); (1163:) C-C chemokine receptor type 3 (C-C CKR-3)(CC-CKR-3) (CCR-3) (CCR3) (CKR3) (Eosinophil eotaxin receptor) (CD193antigen); (1164:) C-C chemokine receptor type 4 (C-C CKR-4) (CC-CKR-4)(CCR-4) (CCR4) (K5-5); (1165:) C-C chemokine receptor type 5 (C-C CKR-5)(CC-CKR-5) (CCR-5) (CCR5) (HIV-1 fusion coreceptor) (CHEMR13) (CD195antigen); (1166:) C-C chemokine receptor type 6 (C-C CKR-6) (CC-CKR-6)(CCR-6) (LARC receptor) (GPR-CY4) (GPRCY4) (Chemokine receptor-like 3)(CKR-L3) (DRY 6) (G-protein coupled receptor 29) (CD196 antigen);(1167:) C-C chemokine receptor type 7 precursor (C-C CKR-7) (CC-CKR-7)(CCR-7) (MIP-3 beta receptor) (EBV-induced G-protein coupled receptor 1)(EBI1) (BLR2) (CD197 antigen) (CDw197); (1168:) C-C chemokine receptortype 8 (C-C CKR-8) (CC-CKR-8) (CCR-8) (GPR-CY6) (GPRCY6) (Chemokinereceptor-like 1) (CKR-L1) (TER1) (CMKBRL2) (CC-chemokine receptorCHEMR1) (CDw198 antigen); (1169:) C-C chemokine receptor type 9 (C-CCKR-9) (CC-CKR-9) (CCR-9) (GPR-9-6) (G-protein coupled receptor 28)(CDw199 antigen); (1170:) C-C chemokine receptor-like 2 (Putative MCP-1chemokine receptor) (Chemokine receptor CCR11) (Chemokine receptor X);(1171:) CCR4-NOT transcription complex, subunit 4 isoform a [Homosapiens]; (1172:) CCR4-NOT transcription complex, subunit 4 isoform b[Homo sapiens]; (1173:) CD160 antigen precursor (Natural killer cellreceptor BY55); (1174:) CD180 antigen precursor (Lymphocyte antigen 64)(Radio protective 106 kDa protein); (1175:) CD200 antigen isoform aprecursor [Homo sapiens]; (1176:) CD200 antigen isoform b [Homosapiens]; (1177:) CD209 antigen (Dendritic cell-specific ICAM-3-grabbingnonintegrin1) (DC-SIGN1) (DC-SIGN) (C-type lectin domain family 4 memberL); (1178:) CD226 antigen precursor (DNAX accessory molecule 1)(DNAM-1); (1179:) CD2-associated protein (Cas ligand with multiple SH3domains) (Adapter protein CMS); (1180:) CD38 antigen [Homo sapiens];(1181:) CD40 antigen isoform 1 precursor [Homo sapiens]; (1182:) CD40antigen isoform 2 precursor [Homo sapiens]; (1183:) CD44 antigenprecursor (Phagocytic glycoprotein 1) (PGP-1) (HUTCH-I) (Extracellularmatrix receptor-III) (ECMR-III) (GP90lymphocyte homing/adhesionreceptor) (Hermes antigen) (Hyaluronate receptor) (Heparan sulfateproteoglycan) (Epican) (CDw44); (1184:) CD53 antigen [Homo sapiens];(1185:) CD63 antigen isoform A [Homo sapiens]; (1186:) CD63 antigenisoform B [Homo sapiens]; (1187:) CD97 antigen precursor (Leukocyteantigen CD97); (1188:) CDC16 homolog [Homo sapiens]; (1189:) CDC26subunit of anaphase promoting complex [Homo sapiens]; (1190:) Cdc34[Homo sapiens]; (1191:) Cdk5 and Abl enzyme substrate 1 [Homo sapiens];(1192:) Cdk5 and Abl enzyme substrate 2 [Homo sapiens]; (1193:) CDK5 andABL1 enzyme substrate 1 (Interactor with CDK3 1) (Ik3-1); (1194:) CDK5and ABL1 enzyme substrate 2 (Interactor with CDK32) (Ik3-2); (1195:)CDP-diacylglycerol-inositol 3-phosphatidyltransferase(Phosphatidylinositol synthase) (PtdIns synthase) (PI synthase); (1196:)Cell division control protein 2 homolog (p34 protein kinase)(Cyclin-dependent kinase 1) (CDK1); (1197:) Cell division controlprotein 42 homolog precursor (G25KGTP-binding protein); (1198:) celldivision cycle 2 protein isoform 1 [Homo sapiens]; (1199:) cell divisioncycle 2 protein isoform 2 [Homo sapiens]; (1200:) cell division cycle2-like 1 (PITSLRE proteins) isoform 1 [Homo sapiens]; (1201:) celldivision cycle 2-like 1 (PITSLRE proteins) isoform 2 [Homo sapiens];(1202:) cell division cycle 2-like 1 (PITSLRE proteins) isoform 3 [Homosapiens]; (1203:) cell division cycle 2-like 1 (PITSLRE proteins)isoform 4 [Homo sapiens]; (1204:) cell division cycle 2-like 1 (PITSLREproteins) isoform 5 [Homo sapiens]; (1205:) cell division cycle 2-like 1(PITSLRE proteins) isoform 6 [Homo sapiens]; (1206:) cell division cycle2-like 1 (PITSLRE proteins) isoform 8 [Homo sapiens]; (1207:) celldivision cycle 2-like 1 (PITSLRE proteins) isoform 9 [Homo sapiens];(1208:) Cell division cycle 34 [Homo sapiens]; (1209:) Cell divisioncycle 34 homolog (S. cerevisiae) [Homo sapiens]; (1210:) cell divisioncycle protein 23 [Homo sapiens]; (1211:) cell division cycle protein 27[Homo sapiens]; (1212:) Cell division protein kinase 2 (p33 proteinkinase); (1213:) Cell division protein kinase 4 (Cyclin-dependent kinase4) (PSK-J3); (1214:) Cell division protein kinase 7 (CDK-activatingkinase) (CAK) (TFIIHbasal transcription factor complex kinase subunit)(39 kDa protein kinase) (P39 Mo15) (STK1) (CAK1); (1215:) Cell surfaceglycoprotein OX2 receptor precursor (CD200 cell surface glycoproteinreceptor); (1216:) Centaurin-gamma 1 (ARF-GAP with GTP-bindingprotein-like, ankyrin repeat and pleckstrin homology domains 2) (AGAP-2)(Phosphatidylinositol-3-kinase enhancer) (PIKE) (GTP-binding andGTPase-activating protein 2) (GGAP2); (1217:) Centaurin-gamma 2 (ARF-GAPwith GTP-binding protein-like, ankyrin repeat and pleckstrin homologydomains 1) (AGAP-1) (GTP-binding and GTPase-activating protein 1)(GGAP1); (1218:) Centaurin-gamma 3 (ARF-GAP with GTP-bindingprotein-like, ankyrin repeat and pleckstrin homology domains 3) (AGAP-3)(MR1-interacting protein) (MRIP-1) (CRAM-associated GTPase) (CRAG);(1219:) CGI-02 protein [Homo sapiens]; (1220:) CGI-11 protein [Homosapiens]; (1221:) CGI-76 protein [Homo sapiens]; (1222:) cGMP-dependentprotein kinase 1, alpha isozyme (CGK 1 alpha) (cGKI-alpha); (1223:)cGMP-dependent protein kinase 1, beta isozyme (cGK 1 beta) (cGKI-beta);(1224:) cGMP-dependent protein kinase 2 (CGK 2) (cGKII) (Type IIcGMP-dependent protein kinase); (1225:) cGMP-inhibited 3′,5′-cyclicphosphodiesterase A (Cyclic GMP-inhibited phosphodiesterase A) (CGI-PDEA); (1226:) cGMP-inhibited 3′,5′-cyclic phosphodiesterase B (CyclicGMP-inhibited phosphodiesterase B) (CGI-PDE B) (CGIPDE1) (CGIP1);(1227:) cGMP-specific 3′,5′-cyclic phosphodiesterase (CGB-PDE)(cGMP-binding cGMP-specific phosphodiesterase); (1228:) CHCHD2 protein[Homo sapiens]; (1229:) CHCHD4 protein [Homo sapiens]; (1230:) chemokine(C-C motif) ligand 14 isoform 1 precursor [Homo sapiens]; (1231:)chemokine (C-C motif) ligand 14 isoform 2 precursor [Homo sapiens];(1232:) chemokine (C-C motif) ligand 7 precursor [Homo sapiens]; (1233:)chemokine (C-C motif) receptor 2 isoform A [Homo sapiens]; (1234:)chemokine (C-C motif) receptor 2 isoform B [Homo sapiens]; (1235:)chemokine (C-X3-C motif) ligand 1 [Homo sapiens]; (1236:) chemokine(C-X-C motif) ligand 12 (stromal cell-derived factor 1)isoform alpha[Homo sapiens]; (1237:) chemokine (C-X-C motif) ligand 12 (stromalcell-derived factor 1)isoform beta [Homo sapiens]; (1238:) chemokine(C-X-C motif) ligand 12 (stromal cell-derived factor 1)isoform gamma[Homo sapiens]; (1239:) Chemokine receptor-like 1 (G-protein coupledreceptor DEZ) (G-protein coupled receptor ChemR23); (1240:) Chemokinereceptor-like 2 (G-protein coupled receptor 30) (IL8-related receptorDRY12) (Flow-induced endothelial G-protein coupled receptor) (FEG-1)(GPCR-BR); (1241:) Chemokine XC receptor 1 (XC chemokine receptor 1)(Lymphotactin receptor) (G-protein coupled receptor 5); (1242:)Chemokine-binding protein 2 (Chemokine-binding protein D6) (C-Cchemokine receptor D6) (Chemokine receptor CCR-9) (Chemokine receptorCCR-10); (1243:) chitotriosidase [Homo sapiens]; (1244:) chitotriosidaseprecursor [Homo sapiens]; (1245:) Chitotriosidase-1 precursor(Chitinase-1); (1246:) chloride channel 6 isoform CIC-6a [Homo sapiens];(1247:) chloride channel 6 isoform CIC-6b [Homo sapiens]; (1248:)chloride channel 6 isoform CIC-6c [Homo sapiens]; (1249:) chloridechannel 6 isoform CIC-6d [Homo sapiens]; (1250:) cholecystokinin Areceptor [Homo sapiens]; (1251:) cholecystokinin preproprotein [Homosapiens]; (1252:) Cholecystokinin type A receptor (CCK-A receptor)(CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R); (1253:) cholesterol25-hydroxylase [Homo sapiens]; (1254:) cholesterol side-chain cleavageenzyme P450scc (EC 1.14.15.67); (1255:) choline acetyltransferase [Homosapiens]; (1256:) choline acetyltransferase isoform 1 [Homo sapiens];(1257:) choline acetyltransferase isoform 2 [Homo sapiens]; (1258:)choline kinase alpha isoform a [Homo sapiens]; (1259:) choline kinasealpha isoform b [Homo sapiens]; (1260:) Choline O-acetyltransferase(CHOACTase) (Choline acetylase) (ChAT); (1261:) cholinephosphotransferase 1 [Homo sapiens]; (1262:) choline/ethanolamine kinaseisoform a [Homo sapiens]; (1263:) choline/ethanolamine kinase isoform b[Homo sapiens]; (1264:) Choline-phosphate cytidylyltransferase A(Phosphorylcholine transferase A) (CTP:phosphocholinecytidylyltransferase A) (CT A) (CCT A) (CCT-alpha); (1265:) cholinephosphotransferase [Homo sapiens]; (1266:) cholinergic receptor,nicotinic, alpha 4 subunit precursor [Homo sapiens]; (1267:)Cholinesterase precursor (Acylcholine acylhydrolase) (CholineesteraseII) (Butyrylcholine esterase) (Pseudocholinesterase); (1268:)chondroitin beta-1,4 N-acetylgalactosaminyltransferase [Homo sapiens];(1269:) chondroitin beta-1,4 N-acetylgalactosaminyltransferase 2 [Homosapiens]; (1270:) Chondroitin beta-1,4-N-acetylgalactosaminyltransferase1(beta4GalNAcT-1); (1271:) Chondroitinbeta-1,4-N-acetylgalactosaminyltransferase 2(GalNAcT-2)(beta4GalNAcT-2); (1272:) chondroitin sulfate proteoglycan 2 (versican)[Homo sapiens]; (1273:) chondroitin sulfate synthase 3 [Homo sapiens];(1274:) chromatin-specific transcription elongation factor large subunit[Homo sapiens]; (1275:) chymase 1, mast cell preproprotein [Homosapiens]; (1276:) Chymase precursor (Mast cell protease I); (1277:)chymotrypsin-like [Homo sapiens]; (1278:) Chymotrypsin-like serineproteinase (LCLP); (1279:) Ciliary neurotrophic factor receptor alphaprecursor (CNTFR alpha); (1280:) citrate synthase precursor, isoform a[Homo sapiens]; (1281:) citrate synthase precursor, isoform b [Homosapiens]; (1282:) Class B basic helix-loop-helix protein 2 (bHLHB2)(Differentially expressed in chondrocytes protein 1) (DEC1)(Enhancer-of-split and hairy-related protein 2) (SHARP-2) (Stimulatedwith retinoic acid 13); (1283:) class I alcohol dehydrogenase, alphasubunit [Homo sapiens]; (1284:) class I alcohol dehydrogenase, gammasubunit [Homo sapiens]; (1285:) class II alcohol dehydrogenase 4 pisubunit [Homo sapiens]; (1286:) class III alcohol dehydrogenase 5 chisubunit [Homo sapiens]; (1287:) class IV alcohol dehydrogenase 7 mu orsigma subunit [Homo sapiens]; (1288:) class IV alcohol dehydrogenase,sigma sigma-ADH; (1289:) clathrin heavy chain 1 [Homo sapiens]; (1290:)CLCN6 [Homo sapiens]; (1291:) CMH-1; (1292:)CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,6-sialyltransferase(Beta-galactoside alpha-2,6-sialyltransferase) (Alpha 2,6-ST)(Sialyltransferase 1) (ST6Gal I) (B-cell antigen CD75); (1293:) CMRF35-Hantigen precursor (CMRF35-H9) (CMRF-35-H9) (CD300a antigen) (Inhibitoryreceptor protein 60) (IRp60) (IRC1/IRC2) (NK inhibitory receptor);(1294:) CMRF35-like-molecule 1 precursor (CLM-1) (Immune receptorexpressed on myeloid cells protein 1) (IREM-1) (Immunoglobulinsuperfamily member 13) (NK inhibitory receptor) (CD300 antigen likefamily member F) (IgSF13); (1295:) c-myc binding protein [Homo sapiens];(1296:) coactivator-associated arginine methyltransferase 1 [Homosapiens]; (1297:) coactosin-like 1 [Homo sapiens]; (1298:) coagulationfactor 11 (thrombin) receptor-like 1 precursor [Homo sapiens]; (1299:)coagulation factor 11 precursor [Homo sapiens]; (1300:) coagulationfactor III precursor [Homo sapiens]; (1301:) coagulation factor IX [Homosapiens]; (1302:) coagulation factor V precursor [Homo sapiens]; (1303:)coagulation factor VII isoform a precursor [Homo sapiens]; (1304:)coagulation factor VII isoform b precursor [Homo sapiens]; (1305:)coagulation factor VIII isoform a precursor [Homo sapiens]; (1306:)coagulation factor VIII isoform b precursor [Homo sapiens]; (1307:)coagulation factor X preproprotein [Homo sapiens]; (1308:) coagulationfactor XIII A1 subunit precursor [Homo sapiens]; (1309:) coagulationfactor XIII B subunit precursor [Homo sapiens]; (1310:) COASY protein[Homo sapiens]; (1311:) Coenzyme A synthase [Homo sapiens]; (1312:)coenzyme A synthase isoform a [Homo sapiens]; (1313:) coenzyme Asynthase isoform b [Homo sapiens]; (1314:) Cofactor required for Sp1transcriptional activation subunit 9(Transcriptional coactivator CRSP33)(RNA polymerase transcriptional regulation mediator subunit 7 homolog)(hMED7) (Activator-recruited cofactor 34 kDa component) (ARC34); (1315:)coilin-interacting nuclear ATPase protein [Homo sapiens]; (1316:)coilin-interacting nuclear ATPase protein [Homo sapiens]; (1317:)Colipase precursor; (1318:) colony stimulating factor 3 isoform aprecursor [Homo sapiens]; (1319:) colony stimulating factor 3 isoform bprecursor [Homo sapiens]; (1320:) colony stimulating factor 3 isoform c[Homo sapiens]; (1321:) colony-stimulating factor; (1322:) complementC1r activated form; (1323:) “Complement C1r subcomponent precursor(Complement component 1, r subcomponent) [Contains:) Complement C1rsubcomponent heavy chain; Complement C1r subcomponent light chain].”;(1324:) complement component 1, s subcomponent [Homo sapiens]; (1325:)complement component 3 precursor [Homo sapiens]; (1326:) Complementcomponent 6 precursor [Homo sapiens]; (1327:) Complement component C1qreceptor precursor (Complement component 1q subcomponent receptor 1)(C1qR) (C1qRp) (C1qR(p)) (C1q/MBL/SPA receptor) (CD93 antigen) (CDw93);(1328:) complement factor D preproprotein [Homo sapiens]; (1329:)Complement receptor type 1 precursor (C3b/C4b receptor) (CD35antigen);(1330:) Complement receptor type 2 precursor (Cr2) (Complement C3dreceptor) (Epstein-Barr virus receptor) (EBV receptor) (CD21 antigen);(1331:) copper monamine oxidase; (1332:) coproporphyrinogen oxidase[Homo sapiens]; (1333:) core 2 beta-1,6-N-acetylglucosaminyltransferase3 [Homo sapiens]; (1334:) corin [Homo sapiens]; (1335:) Corticosteroid11-beta-dehydrogenase isozyme 1 (11-DH) (11-beta-hydroxysteroiddehydrogenase 1) (11-beta-HSD1); (1336:) Corticosteroid11-beta-dehydrogenase isozyme 2 (11-DH2) (11-beta-hydroxysteroiddehydrogenase type 2) (11-beta-HSD2) (NAD-dependent11-beta-hydroxysteroid dehydrogenase); (1337:) Corticotropin-releasingfactor receptor 1 precursor (CRF-R) (CRF1) (Corticotropin-releasinghormone receptor 1) (CRH-R 1); (1338:) Corticotropin-releasing factorreceptor 2 precursor (CRF-R 2) (CRF2) (Corticotropin-releasing hormonereceptor 2) (CRH-R 2); (1339:) COUP transcription factor 1 (COUP-TF1)(COUP-TF I) (V-ERBA-related protein EAR-3); (1340:) COUP transcriptionfactor 2 (COUP-TF2) (COUP-TF II) (Apolipoprotein AI regulatoryprotein 1) (ARP-1); (1341:) COX11 homolog [Homo sapiens]; (1342:)Coxsackievirus and adenovirus receptor precursor (CoxsackievirusB-adenovirus receptor) (hCAR) (CVB3-binding protein) (HCVADR); (1343:)CPA4 protein [Homo sapiens]; (1344:) C-reactive protein,pentraxin-related [Homo sapiens]; (1345:) CREB binding protein [Homosapiens]; (1346:) CRSP complex subunit 2 (Cofactor required for Sp1transcriptional activation subunit 2) (Transcriptional coactivatorCRSP150) (Vitamin D3 receptor-interacting protein complex 150 kDacomponent) (DRIP150) (Thyroid hormone receptor-associated proteincomplex 170 kDa component) (Trap170) (Activator-recruited cofactor 150kDa component) (ARC150); (1347:) CRSP complex subunit 3 (Cofactorrequired for Sp1 transcriptional activation subunit 3) (Transcriptionalcoactivator CRSP130) (Vitamin D3 receptor-interacting protein complex130 kDa component) (DRIP130) (Activator-recruited cofactor 130 kDacomponent) (ARC130); (1348:) CRSP complex subunit 6 (Cofactor requiredfor Sp1 transcriptional activation subunit 6) (Transcriptionalcoactivator CRSP77) (Vitamin D3 receptor-interacting protein complex 80kDa component) (DRIP80) (Thyroid hormone receptor-associated proteincomplex 80 kDa component) (Trap80) (Activator-recruited cofactor 77 kDacomponent) (ARC77); (1349:) CRSP complex subunit 7 (Cofactor requiredfor Sp1 transcriptional activation subunit 7) (Transcriptionalcoactivator CRSP70) (Activator-recruited cofactor 70 kDa component)(ARC70); (1350:) crystallin, alpha A [Homo sapiens]; (1351:) crystallin,alpha B [Homo sapiens]; (1352:) crystallin, beta A2 [Homo sapiens];(1353:) crystallin, beta A3 [Homo sapiens]; (1354:) crystallin, beta A4[Homo sapiens]; (1355:) crystallin, beta B1 [Homo sapiens]; (1356:)crystallin, beta B2 [Homo sapiens]; (1357:) crystallin, beta B3 [Homosapiens]; (1358:) crystallin, gamma A [Homo sapiens]; (1359:)crystallin, gamma B [Homo sapiens]; (1360:) crystallin, gamma C [Homosapiens]; (1361:) crystallin, gamma D [Homo sapiens]; (1362:)crystallin, gamma S [Homo sapiens]; (1363:) crystallin, mu isoform 1[Homo sapiens]; (1364:) crystallin, mu isoform 2 [Homo sapiens]; (1365:)crystallin, zeta [Homo sapiens]; (1366:) c-src tyrosine kinase [Homosapiens]; (1367:) CTP synthase [Homo sapiens]; (1368:) CTP synthase 1(UTP—ammonia ligase 1) (CTP synthetase 1); (1369:) CTP synthase 2(UTP—ammonia ligase 2) (CTP synthetase 2); (1370:) C-type lectin domainfamily 4 member F (C-type lectin superfamily member 13) (C-type lectin13); (1371:) C-type lectin domain family 4 member M (CD209 antigen-likeprotein1) (Dendritic cell-specific ICAM-3-grabbing nonintegrin 2)(DC-SIGN2) (DC-SIGN-related protein) (DC-SIGNR)(Liver/lymphnode-specific ICAM-3-grabbing nonintegrin) (L-SIGN)(CD299antigen); (1372:) C-type lectin domain family 9 member A; (1373:)Cubilin precursor (Intrinsic factor-cobalamin receptor) (Intrinsicfactor-vitamin B12 receptor) (460 kDa receptor) (Intestinal intrinsicfactor receptor); (1374:) Cullin-1 (CUL-1); (1375:) Cullin-2 (CUL-2);(1376:) Cullin-5 (CUL-5) (Vasopressin-activated calcium-mobilizingreceptor) (VACM-1); (1377:) CX3C chemokine receptor 1 (C-X3-C CKR-1)(CX3CR1) (Fractalkine receptor) (G-protein coupled receptor 13) (V28)(Beta chemokine receptor-like 1) (CMK-BRL-1) (CMKBLR1); (1378:) C-X-Cchemokine receptor type 3 (CXC-R3) (CXCR-3) (Interferon-inducibleprotein 10 receptor) (IP-10 receptor) (CKR-L2) (CD183 antigen) (Gprotein-coupled receptor 9); (1379:) C-X-C chemokine receptor type 4(CXC-R4) (CXCR-4) (Stromal cell-derived factor 1 receptor) (SDF-1receptor) (Fusin) (Leukocyte-derived seven transmembrane domainreceptor) (LESTR) (LCR1) (FB22) (NPYRL) (HM89) (CD184 antigen); (1380:)C-X-C chemokine receptor type 5 (CXC-R5) (CXCR-5) (Burkitt lymphomareceptor 1) (Monocyte-derived receptor 15) (MDR-15) (CD185antigen);(1381:) C-X-C chemokine receptor type 6 (CXC-R6) (CXCR-6) (G-proteincoupled receptor bonzo) (G-protein coupled receptor STRL33)(CD186antigen) (CDw186); (1382:) C-X-C chemokine receptor type 7(CXC-R7) (CXCR-7) (G-protein coupled receptor RDC1 homolog) (RDC-1)(Chemokine orphan receptor1) (G-protein coupled receptor 159); (1383:)cyclin D1 [Homo sapiens]; (1384:) cyclin-dependent kinase 2 isoform 1[Homo sapiens]; (1385:) cyclin-dependent kinase 2 isoform 2 [Homosapiens]; (1386:) cyclin-dependent kinase inhibitor 1B [Homo sapiens];(1387:) cyclin-dependent kinase inhibitor 2A isoform 1 [Homo sapiens];(1388:) cyclin-dependent kinase inhibitor 2A isoform 3 [Homo sapiens];(1389:) cyclin-dependent kinase inhibitor 2A isoform 4 [Homo sapiens];(1390:) Cyclin-dependent kinase inhibitor 2A, isoform 4 (p14ARF)(p19ARF); (1391:) Cyclin-dependent kinase-like 5(Serine/threonine-protein kinase 9); (1392:) cyclin-selective ubiquitincarrier protein [Homo sapiens]; (1393:) Cystathionase (cystathioninegamma-lyase) [Homo sapiens]; (1394:) cystathionase isoform 1 [Homosapiens]; (1395:) cystathionase isoform 1 variant [Homo sapiens];(1396:) cystathionase isoform 2 [Homo sapiens]; (1397:) cystathionine Bsynthase [Homo sapiens]; (1398:) Cystathionine beta-synthase (Serinesulfhydrase) (Beta-thionase); (1399:) cystathionine beta-synthase majorisoform [Homo sapiens]; (1400:) cystathionine beta-synthase; (1401:)Cystathionine gamma-lyase (Gamma-cystathionase); (1402:) “cystathioninegamma-lyase; cystathionase [Homo sapiens].”; (1403:)cystathionine-beta-synthase [Homo sapiens]; (1404:) Cystatin C precursor(Neuroendocrine basic polypeptide) (Gamma-trace) (Post-gamma-globulin);(1405:) “cysteine conjugate-beta lyase; cytoplasmic (glutaminetransaminase k, kyneurenine aminotransferase) [Homo sapiens].”; (1406:)cysteine desulfurase [Homo sapiens]; (1407:) Cysteine desulfurase,mitochondrial precursor; (1408:) cysteine dioxygenase [Homo sapiens];(1409:) Cysteine protease ATG4A (Autophagy-related protein 4 homolog A)(hAPG4A) (Autophagin-2) (Autophagy-related cysteine endopeptidase 2)(AUT-like 2 cysteine endopeptidase); (1410:) Cysteine protease ATG4B(Autophagy-related protein 4 homolog B) (hAPG4B) (Autophagin-1)(Autophagy-related cysteine endopeptidase 1) (AUT-like 1 cysteineendopeptidase); (1411:) Cysteine protease ATG4C (Autophagy-relatedprotein 4 homolog C) (Autophagin-3) (Autophagy-related cysteineendopeptidase 3) (AUT-like 3 cysteine endopeptidase); (1412:) Cysteineprotease ATG4D (Autophagy-related protein 4 homolog D) (Autophagin-4)(Autophagy-related cysteine endopeptidase 4) (AUT-like 4 cysteineendopeptidase); (1413:) cysteine protease CPP32 isoform alpha; (1414:)cysteine protease CPP32 isoform beta; (1415:) cysteine protease Mch2isoform alpha; (1416:) cysteine protease Mch2 isoform beta; (1417:)cysteine protease; (1418:) cysteine-rich, angiogenic inducer, 61 [Homosapiens]; (1419:) Cysteinyl leukotriene receptor 1 (CysLTR1) (Cysteinylleukotriene D4 receptor) (LTD4 receptor) (HG55) (HMTMF81); (1420:)Cysteinyl leukotriene receptor 2 (CysLTR2) (HG57) (HPN321) (hGPCR21);(1421:) cytidine 5′-monophosphate N-acetylneuraminic acid synthetase[Homo sapiens]; (1422:) Cytidine deaminase (Cytidine aminohydrolase);(1423:) cytidine deaminase [Homo sapiens]; (1424:) Cytidinemonophosphate-N-acetylneuraminic acid hydroxylase-like protein(CMP-NeuAc hydroxylase-like protein); (1425:) cytidine triphosphatesynthase 11 [Homo sapiens]; (1426:) cytidylate kinase [Homo sapiens];(1427:) cytochrome b [Homo sapiens]; (1428:) cytochrome b, alphapolypeptide [Homo sapiens]; (1429:) Cytochrome b; (1430:) cytochrome b5reductase b5R.2 [Homo sapiens]; (1431:) cytochrome b5 reductase isoform1 [Homo sapiens]; (1432:) cytochrome b5 reductase isoform 2 [Homosapiens]; (1433:) cytochrome c [Homo sapiens]; (1434:) Cytochrome coxidase subunit 1 (Cytochrome c oxidase polypeptideI); (1435:)Cytochrome c oxidase subunit 2 (Cytochrome c oxidase polypeptideII);(1436:) Cytochrome c oxidase subunit 3 (Cytochrome c oxidasepolypeptideIII); (1437:) cytochrome c oxidase subunit 8A [Homo sapiens];(1438:) cytochrome c oxidase subunit IV isoform 1 precursor [Homosapiens]; (1439:) cytochrome c oxidase subunit IV isoform 2 [Homosapiens]; (1440:) cytochrome c oxidase subunit IV precursor [Homosapiens]; (1441:) cytochrome c oxidase subunit Va precursor [Homosapiens]; (1442:) cytochrome c oxidase subunit Vb precursor [Homosapiens]; (1443:) cytochrome c oxidase subunit VIa polypeptide 1precursor [Homo sapiens]; (1444:) cytochrome c oxidase subunit Viapolypeptide 2 precursor [Homo sapiens]; (1445:) cytochrome c oxidasesubunit VIb [Homo sapiens]; (1446:) cytochrome c oxidase subunit VIcproprotein [Homo sapiens]; (1447:) cytochrome c-1 [Homo sapiens];(1448:) cytochrome P450 [Homo sapiens]; (1449:) Cytochrome P450 11A1,mitochondrial precursor (CYPXIA1) (P450(scc)) (Cholesterol side-chaincleavage enzyme) (Cholesterol desmolase); (1450:) Cytochrome P450 11B2,mitochondrial precursor (CYPXIB2) (P-450Aldo) (Aldosterone synthase)(ALDOS) (Aldosterone-synthesizing enzyme) (Steroid 18-hydroxylase)(P-450C18); (1451:) Cytochrome P450 17A1 (CYPXVII) (P450-C17) (P450c17)(Steroid 17-alpha-monooxygenase) (Steroid 17-alpha-hydroxylase/17,20lyase); (1452:) Cytochrome P450 19A1 (Aromatase) (CYPXIX) (Estrogensynthetase) (P-450AROM); (1453:) Cytochrome P450 1A1 (CYPIA1) (P450-P1)(P450 form 6) (P450-C); (1454:) cytochrome P450 1A1 variant [Homosapiens]; (1455:) Cytochrome P450 1A2 (CYPIA2) (P450-P3) (P(3)-450)(P450 4); (1456:) Cytochrome P450 1B1 (CYPIB1); (1457:) Cytochrome P45021 (Cytochrome P450 XXI) (Steroid 21-hydroxylase) (21-OHase) (P450-C21)(P-450c21) (P450-C21B); (1458:) Cytochrome P450 26A1 (Retinoicacid-metabolizing cytochrome) (P450 retinoic acid-inactivating 1)(P450RAI) (hP450RAI) (Retinoic acid-4-hydroxylase); (1459:) CytochromeP450 26B1 (P450 26A2) (P450 retinoic acid-inactivating 2) (P450RAI-2)(Retinoic acid-metabolizing cytochrome); (1460:) Cytochrome P450 27,mitochondrial precursor (Cytochrome P-450C27/25) (Sterol 26-hydroxylase)(Sterol 27-hydroxylase) (Vitamin D(3) 25-hydroxylase)(5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol 27-hydroxylase);(1461:) cytochrome P450 2A3, hepatic—human (fragment); (1462:)Cytochrome P450 2A7 (CYPIIA7) (P450-11A4); (1463:) Cytochrome P450 2B6(CYPIIB6) (P450 IIB1); (1464:) Cytochrome P450 2C18 (CYPIIC18)(P450-6B/29C); (1465:) Cytochrome P450 2C8 (CYPIIC8) (P450 form 1)(P450MP-12/MP-20) (P450 IIC2) (S-mephenyloin 4-hydroxylase); (1466:)Cytochrome P450 2C9 ((R)-limonene 6-monooxygenase) ((S)-limonene6-monooxygenase) ((S)-limonene 7-monooxygenase) (CYPIIC9) (P450PB-1)(P450MP-4/MP-8) (S-mephenyloin 4-hydroxylase) (P-450 MP); (1467:)Cytochrome P450 2E1 (CYPIIE1) (P450-J); (1468:) Cytochrome P450 2J2(CYPIIJ2) (Arachidonic acid epoxygenase); (1469:) Cytochrome P450 2R1(Vitamin D 25-hydroxylase); (1470:) Cytochrome P450 3A3 (CYPIIIA3)(HLp); (1471:) Cytochrome P450 3A4 (Quinine 3-monooxygenase) (CYPIIIA4)(Nifedipine oxidase) (Taurochenodeoxycholate 6-alpha-hydroxylase)(NF-25) (P450-PCN1); (1472:) Cytochrome P450 3A5 (CYPIIIA5) (P450-PCN3)(HLp2); (1473:) Cytochrome P450 3A7 (CYPIIIA7) (P450-HFLA); (1474:)Cytochrome P450 4A11 precursor (CYPIVAII) (Fatty acid omega-hydroxylase)(P-450 HK omega) (Lauric acid omega-hydroxylase) (CYP4AII)(P450-HL-omega); (1475:) Cytochrome P450 4B1 (CYPIVB1) (P450-HP);(1476:) Cytochrome P450 4F2 (CYPIVF2) (Leukotriene-B(4)omega-hydroxylase) (Leukotriene-B(4) 20-monooxygenase) (CytochromeP450-LTB-omega); (1477:) Cytochrome P450 4F3 (CYPIVF3) (Leukotriene-B(4)omega-hydroxylase) (Leukotriene-B(4) 20-monooxygenase) (CytochromeP450-LTB-omega); (1478:) cytochrome P450 family 1 subfamily Apolypeptide 1 [Homo sapiens]; (1479:) cytochrome P450 family 3 subfamilyA polypeptide 4 [Homo sapiens]; (1480:) cytochrome P450 reductase [Homosapiens]; (1481:) cytochrome P450, family 1, subfamily A, polypeptide 1[Homo sapiens]; (1482:) cytochrome P450, family 1, subfamily A,polypeptide 2 [Homo sapiens]; (1483:) cytochrome P450, family 1,subfamily B, polypeptide 1 [Homo sapiens]; (1484:) cytochrome P450,family 11, subfamily B, polypeptide 1 isoform 1 precursor [Homosapiens]; (1485:) cytochrome P450, family 11, subfamily B, polypeptide 1isoform 2precursor [Homo sapiens]; (1486:) cytochrome P450, family 17[Homo sapiens]; (1487:) cytochrome P450, family 19 [Homo sapiens];(1488:) cytochrome P450, family 2, subfamily A, polypeptide 6 [Homosapiens]; (1489:) cytochrome P450, family 2, subfamily B, polypeptide 6[Homo sapiens]; (1490:) cytochrome P450, family 2, subfamily C,polypeptide 18 [Homo sapiens]; (1491:) cytochrome P450, family 2,subfamily C, polypeptide 19 [Homo sapiens]; (1492:) cytochrome P450,family 2, subfamily C, polypeptide 8 [Homo sapiens]; (1493:) cytochromeP450, family 2, subfamily C, polypeptide 9 [Homo sapiens]; (1494:)cytochrome P450, family 2, subfamily D, polypeptide 6 isoform 1 [Homosapiens]; (1495:) cytochrome P450, family 2, subfamily D, polypeptide 6isoform 2 [Homo sapiens]; (1496:) cytochrome P450, family 2, subfamilyE, polypeptide 1 [Homo sapiens]; (1497:) cytochrome P450, family 2,subfamily J, polypeptide 2 [Homo sapiens]; (1498:) cytochrome P450,family 2, subfamily R, polypeptide 1 [Homo sapiens]; (1499:) cytochromeP450, family 2, subfamily U, polypeptide 1 [Homo sapiens]; (1500:)cytochrome P450, family 2, subfamily W, polypeptide 1 [Homo sapiens];(1501:) cytochrome P450, family 21, subfamily A, polypeptide 2 [Homosapiens]; (1502:) cytochrome P450, family 24 precursor [Homo sapiens];(1503:) cytochrome P450, family 26, subfamily A, polypeptide 1 isoform 1[Homo sapiens]; (1504:) cytochrome P450, family 26, subfamily A,polypeptide 1 isoform 2 [Homo sapiens]; (1505:) cytochrome P450, family26, subfamily b, polypeptide 1 [Homo sapiens]; (1506:) cytochrome P450,family 26, subfamily C, polypeptide 1 [Homo sapiens]; (1507:) cytochromeP450, family 27, subfamily A, polypeptide 1 precursor[Homo sapiens];(1508:) cytochrome P450, family 27, subfamily B, polypeptide 1 [Homosapiens]; (1509:) cytochrome P450, family 3, subfamily A, polypeptide 43isoform 1 [Homo sapiens]; (1510:) cytochrome P450, family 3, subfamilyA, polypeptide 43 isoform 2 [Homo sapiens]; (1511:) cytochrome P450,family 3, subfamily A, polypeptide 43 isoform 3 [Homo sapiens]; (1512:)cytochrome P450, family 3, subfamily A, polypeptide 5 [Homo sapiens];(1513:) cytochrome P450, family 3, subfamily A, polypeptide 7 [Homosapiens]; (1514:) cytochrome P450, family 4, subfamily A, polypeptide 11[Homo sapiens]; (1515:) cytochrome P450, family 4, subfamily F,polypeptide 12 [Homo sapiens]; (1516:) cytochrome P450, family 4,subfamily F, polypeptide 2 [Homo sapiens]; (1517:) cytochrome P450,family 4, subfamily F, polypeptide 3 [Homo sapiens]; (1518:) cytochromeP450, family 46 [Homo sapiens]; (1519:) cytochrome P450, family 7,subfamily A, polypeptide 1 [Homo sapiens]; (1520:) cytochrome P450,family 7, subfamily B, polypeptide 1 [Homo sapiens]; (1521:) cytochromeP450, subfamily IIIA, polypeptide 4 [Homo sapiens]; (1522:) cytochromeP450, subfamily XIA precursor [Homo sapiens]; (1523:) cytochrome P450,subfamily XIB polypeptide 2 precursor [Homo sapiens]; (1524:) cytochromeP450; (1525:) cytochrome P450j; (1526:) Cytokine receptor common betachain precursor (GM-CSF/IL-3/1L-5receptor common beta-chain) (CD131antigen) (CDw131); (1527:) Cytokine receptor common gamma chainprecursor (Gamma-C) (Interleukin-2 receptor gamma chain) (IL-2R gammachain) (p64) (CD132 antigen); (1528:) Cytokine receptor-like factor 1precursor (Cytokine-like factor 1) (CLF-1) (ZcytoR5); (1529:) Cytokinereceptor-like factor 2 precursor (Cytokine receptor-like2) (CRL2)(IL-XR) (Thymic stromal lymphopoietin protein receptor) (TSLPR); (1530:)cytoplasmic cysteine conjugate-beta lyase [Homo sapiens]; (1531:)Cytoplasmic dynein 1 light intermediate chain 1 (Dynein lightintermediate chain 1, cytosolic) (Dynein light chain A) (DLC-A); (1532:)Cytosol aminopeptidase (Leucine aminopeptidase) (LAP) (Leucylaminopeptidase) (Proline aminopeptidase) (Prolyl aminopeptidase)(Peptidase S); (1533:) Cytosolic 5′-nucleotidase 1A (Cytosolic5′-nucleotidase IA) (cN1A) (cN-IA) (cN-1); (1534:) Cytosolic5′-nucleotidase 1B (Cytosolic 5′-nucleotidase IB) (cN1B) (cN-IB)(Autoimmune infertility-related protein); (1535:) cytosolic acetyl-CoAhydrolase [Homo sapiens]; (1536:) cytosolic aminopeptidase P [Homosapiens]; (1537:) Cytosolic beta-glucosidase (Cytosolicbeta-glucosidase-like protein1); (1538:) cytosolic beta-glucosidase[Homo sapiens]; (1539:) cytosolic inhibitor of NRF2 [Homo sapiens];(1540:) cytosolic leucyl-tRNA synthetase [Homo sapiens]; (1541:)cytosolic malic enzyme 1 [Homo sapiens]; (1542:) cytosolic malic enzyme1 variant [Homo sapiens]; (1543:) cytosolic malic enzyme; (1544:)cytosolic NADP(+)-dependent malic enzyme; (1545:) cytosolic ovariancarcinoma antigen 1 isoform a [Homo sapiens]; (1546:) cytosolic ovariancarcinoma antigen 1 isoform b [Homo sapiens]; (1547:) cytosolicphosphoenolpyruvate carboxykinase 1 [Homo sapiens]; (1548:) “Cytosolicphospholipase A2 (cPLA2) (Phospholipase A2 group IVA)[Includes:)Phospholipase A2 (Phosphatidylcholine 2-acylhydrolase);Lysophospholipase].”; (1549:) Cytosolic phospholipase A2 beta(cPLA2-beta) (Phospholipase A2 group IVB); (1550:) Cytosolicphospholipase A2 delta (cPLA2-delta) (Phospholipase A2 group IVD);(1551:) Cytosolic phospholipase A2 epsilon (cPLA2-epsilon)(Phospholipase A2 group IVE); (1552:) Cytosolic phospholipase A2 gammaprecursor (cPLA2-gamma) (Phospholipase A2 group IVC); (1553:) Cytosolicphospholipase A2 zeta (cPLA2-zeta) (Phospholipase A2 group IVF); (1554:)cytosolic phospholipase A2, group IVA [Homo sapiens]; (1555:) Cytosolicpurine 5′-nucleotidase (5′-nucleotidase cytosolic 11); (1556:) cytosolicthyroid hormone-binding protein (EC 2.7.1.40); (1557:) CAAX prenylprotease 1 homolog (Prenyl protein-specific endoprotease 1)(Farnesylated proteins-converting enzyme 1) (FACE-1) (Zincmetalloproteinase Step 24 homolog); (1558:) CAAX prenyl protease 2(Prenyl protein-specific endoprotease 2) (Farnesylatedproteins-converting enzyme 2) (FACE-2) (hRCE1); (1559:) D(1A) dopaminereceptor; (1560:) D(1B) dopamine receptor (D(5) dopamine receptor)(D1beta dopamine receptor); (1561:) D(2) dopamine receptor (Dopamine D2receptor); (1562:) D(3) dopamine receptor; (1563:) D(4) dopaminereceptor (Dopamine D4 receptor) (D(2C) dopamine receptor); (1564:)D-2-hydroxyglutarate dehydrogenase, mitochondrial precursor; (1565:)dachshund homolog 1 isoform a [Homo sapiens]; (1566:) dachshund homolog1 isoform b [Homo sapiens]; (1567:) dachshund homolog 1 isoform c [Homosapiens]; (1568:) D-amino-acid oxidase [Homo sapiens]; (1569:)D-aspartate oxidase isoform a [Homo sapiens]; (1570:) D-aspartateoxidase isoform b [Homo sapiens]; (1571:) D-beta-hydroxybutyratedehydrogenase, mitochondrial precursor (BDH) (3-hydroxybutyratedehydrogenase); (1572:) DCP1 decapping enzyme homolog A [Homo sapiens];(1573:) DCP1 decapping enzyme homolog B (S. cerevisiae) [Homo sapiens];(1574:) DCP2 decapping enzyme [Homo sapiens]; (1575:) D-dopachromedecarboxylase (D-dopachrome tautomerase) (Phenylpyruvate tautomeraseII); (1576:) D-dopachrome tautomerase [Homo sapiens]; (1577:) DEAD/H(Asp-Glu-Ala-Asp/His) box polypeptide 11 isoform 1 [Homo sapiens];(1578:) DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 isoform 2 [Homosapiens]; (1579:) deaminase, adenosine; (1580:) Death-associated proteinkinase 1 (DAP kinase 1); (1581:) Death-associated protein kinase 2 (DAPkinase 2) (DAP-kinase-related protein 1) (DRP-1); (1582:) Debranchingenzyme homolog 1 (S. cerevisiae) [Homo sapiens]; (1583:) debranchingenzyme homolog 1 [Homo sapiens]; (1584:) decapping enzyme Dcp1b [Homosapiens]; (1585:) decapping enzyme hDcp1a [Homo sapiens]; (1586:)decapping enzyme hDcp1b [Homo sapiens]; (1587:) decapping enzyme hDcp2[Homo sapiens]; (1588:) Decapping enzyme, scavenger [Homo sapiens];(1589:) defender against cell death 1 [Homo sapiens]; (1590:) defensin,alpha 5 preproprotein [Homo sapiens]; (1591:) Dehydrogenase/reductaseSDR family member 8 precursor (17-beta-hydroxysteroid dehydrogenase 11)(17-beta-HSD 11) (17-beta-HSDXI) (17betaHSDXI) (17bHSD11) (17betaHSD11)(Retinal short-chain dehydrogenase/reductase 2) (retSDR2) (CutaneousT-cell lymphoma-associated antigen HD-CL-03) (CTCL tumor antigenHD-CL-03); (1592:) deiodinase, iodothyronine, type I isoform a [Homosapiens]; (1593:) deiodinase, iodothyronine, type I isoform b [Homosapiens]; (1594:) deiodinase, iodothyronine, type I isoform c [Homosapiens]; (1595:) deiodinase, iodothyronine, type I isoform d [Homosapiens]; (1596:) deiodinase, iodothyronine, type II isoform a [Homosapiens]; (1597:) deiodinase, iodothyronine, type II isoform b [Homosapiens]; (1598:) deiodinase, iodothyronine, type III [Homo sapiens];(1599:) “Delta 1-pyrroline-5-carboxylate synthetase (P5CS)(Aldehydedehydrogenase 18 family member A1) [Includes:) Glutamate5-kinase (Gamma-glutamyl kinase) (GK); Gamma-glutamyl phosphatereductase (GPR) (Glutamate-5-semialdehyde dehydrogenase)(Glutamyl-gamma-semialdehyde dehydrogenase)].”; (1600:) delta4-3-oxosteroid 5 beta-reductase [Homo sapiens]; (1601:)delta-aminolevulinate synthase (housekeeping) [Homo sapiens]; (1602:)Delta and Notch-like epidermal growth factor-related receptor precursor;(1603:) delta isoform of regulatory subunit B56, protein phosphatase 2Aisoform 1 [Homo sapiens]; (1604:) delta isoform of regulatory subunitB56, protein phosphatase 2A isoform 2 [Homo sapiens]; (1605:) deltaisoform of regulatory subunit B56, protein phosphatase 2A isoform 3[Homo sapiens]; (1606:) Delta-1-pyrroline-5-carboxylate dehydrogenase,mitochondrial precursor (P5C dehydrogenase) (Aldehyde dehydrogenase4A1); (1607:) delta3, delta2-enoyl-CoA isomerase; (1608:)Delta-4-3-oxosteroid 5beta reductase; (1609:) Delta-aminolevulinic aciddehydratase (Porphobilinogen synthase) (ALADH); (1610:)delta-aminolevulinic acid dehydratase isoform a [Homo sapiens]; (1611:)delta-amino; evulinic acid dehydratase isoform b [Homo sapiens]; (1612:)Delta-type opioid receptor (DOR-1); (1613:) deoxy-5′-nucleotidase [Homosapiens]; (1614:) deoxycytidine kinase [Homo sapiens]; (1615:)Deoxycytidylate deaminase (dCMP deaminase); (1616:) deoxycytidylatedeaminase; (1617:) deoxyguanosine kinase isoform a precursor [Homosapiens]; (1618:) deoxyguanosine kinase isoform b precursor [Homosapiens]; (1619:) Deoxyhypusine hydroxylase (Deoxyhypusinemonooxygenase) (hDOHH) (HEAT-like repeat-containing protein 1); (1620:)Deoxyhypusine synthase (DHS); (1621:) deoxyhypusine synthase isoform a[Homo sapiens]; (1622:) deoxyhypusine synthase isoform b [Homo sapiens];(1623:) deoxyhypusine synthase isoform c [Homo sapiens]; (1624:)deoxyhypusine synthase; (1625:) Deoxyribonuclease gamma precursor (DNasegamma) (DeoxyribonucleaseI-like 3) (DNase I homolog protein DHP2) (Liverand spleen DNase) (LS-DNase) (LSD); (1626:) deoxyribonuclease Iprecursor [Homo sapiens]; (1627:) deoxyribonuclease II, lysosomalprecursor [Homo sapiens]; (1628:) deoxyribonuclease III (DNase III)[Homo sapiens]; (1629:) Deoxyribonuclease-2-alpha precursor(Deoxyribonuclease II alpha) (DNase II alpha) (Acid DNase) (LysosomalDNase II) (R31240_(—)2); (1630:) Deoxyuridine 5′-triphosphatenucleotidohydrolase, mitochondrial precursor (dUTPase) (dUTPpyrophosphatase); (1631:) de-ubiquitinase [Homo sapiens]; (1632:)deubiquitinating enzyme [Homo sapiens]; (1633:) deubiquitinating enzyme1 [Homo sapiens]; (1634:) deubiquitinating enzyme 3 [Homo sapiens];(1635:) deubiquitinating enzyme DUB1 [Homo sapiens]; (1636:)deubiquitinating enzyme DUB2 [Homo sapiens]; (1637:) deubiquitinatingenzyme DUB4 [Homo sapiens]; (1638:) Deubiquitinating Enzyme Uch-L3(Human) At 1.8 Angstrom Resolution; (1639:) Deubiquitinating proteinVCIP135 (Valosin-containing protein p97/p47 complex-interacting proteinp135) (Valosin-containing protein p97/p47 complex-interacting protein1); (1640:) D-glucuronyl C5-epimerase [Homo sapiens]; (1641:)Diacylglycerol kinase alpha (Diglyceride kinase alpha) (DGK-alpha) (DAGkinase alpha) (80 kDa diacylglycerol kinase); (1642:) Diacylglycerolkinase beta (Diglyceride kinase beta) (DGK-beta) (DAG kinase beta) (90kDa diacylglycerol kinase); (1643:) Diacylglycerol kinase delta(Diglyceride kinase delta) (DGK-delta) (DAG kinase delta) (130 kDadiacylglycerol kinase); (1644:) Diacylglycerol kinase gamma (Diglyceridekinase gamma) (DGK-gamma) (DAG kinase gamma); (1645:) diacylglycerolkinase gamma [Homo sapiens]; (1646:) Diacylglycerol kinase kappa(Diglyceride kinase kappa) (DGK-kappa) (DAG kinase kappa) (142 kDadiacylglycerol kinase); (1647:) diacylglycerol kinase, beta isoform 1[Homo sapiens]; (1648:) diacylglycerol kinase, beta isoform 2 [Homosapiens]; (1649:) diacylglycerol kinase, delta 130 kDa isoform 1 [Homosapiens]; (1650:) diacylglycerol kinase, delta 130 kDa isoform 2 [Homosapiens]; (1651:) diacylglycerol kinase, eta isoform 1 [Homo sapiens];(1652:) diacylglycerol kinase, eta isoform 2 [Homo sapiens]; (1653:)diacylglycerol kinase, gamma 90 kDa [Homo sapiens]; (1654:)diacylglycerol kinase, iota [Homo sapiens]; (1655:) diacylglycerolO-acyltransferase 1 [Homo sapiens]; (1656:) DiacylglycerolO-acyltransferase 2 (Diglyceride acyltransferase 2); (1657:)diacylglycerol O-acyltransferase 2-like 4 [Homo sapiens]; (1658:)Diamine acetyltransferase 1 (Spermidine/spermineN(1)-acetyltransferase 1) (SSAT) (SSAT-1) (Putrescine acetyltransferase)(Polyamine N-acetyltransferase 1); (1659:) Diamine acetyltransferase 2(Spermidine/spermine N(1)-acetyltransferase 2) (PolyamineN-acetyltransferase 2); (1660:) diamine oxidase, copper/topa quinonecontaining; (1661:) diamine oxidase; (1662:) dicarbonyl/L-xylulosereductase [Homo sapiens]; (1663:) dicer 1 [Homo sapiens]; (1664:)dihydrofolate reductase [Homo sapiens]; (1665:) Dihydrofolate reductase;(1666:) dihydrolipoamide acetyltransferase; (1667:) “dihydrolipoamidebranched chain transacylase (E2 component of branched chain keto aciddehydrogenase complex; maple syrup urine disease) [Homo sapiens].”;(1668:) Dihydrolipoamide branched chain transacylase E2 [Homo sapiens];(1669:) dihydrolipoamide branched chain transacylase precursor [Homosapiens]; (1670:) dihydrolipoamide dehydrogenase precursor [Homosapiens]; (1671:) dihydrolipoamide dehydrogenase-binding protein [Homosapiens]; (1672:) dihydrolipoamide S-acetyltransferase (E2 component ofpyruvate dehydrogenase complex) [Homo sapiens]; (1673:) dihydrolipoamideS-acetyltransferase (E2 component of pyruvate dehydrogenase complex)variant [Homo sapiens]; (1674:) dihydrolipoamide S-succinyltransferase(E2 component of 2-oxo-glutarate complex) [Homo sapiens]; (1675:)dihydrolipoamide S-succinyltransferase (EC 2.3.1.61)-human; (1676:)dihydrolipoamide succinyltransferase [Homo sapiens]; (1677:)dihydrolipoamide succinyltransferase; (1678:) Dihydrolipoyldehydrogenase, mitochondrial precursor (Dihydrolipoamide dehydrogenase)(Glycine cleavage system L protein); (1679:) dihydrolipoyl transacylase;(1680:) Dihydrolipoyllysine-residue acetyltransferase component ofpyruvate dehydrogenase complex, mitochondrial precursor (Pyruvatedehydrogenase complex E2 subunit) (PDCE2) (E2) (DihydrolipoamideS-acetyltransferase component of pyruvate dehydrogenase complex)(PDC-E2) (70 kDa mitochondrial autoantigen of primary biliary cirrhosis)(PBC) (M2 antigen complex 70 kDa subunit); (1681:)Dihydrolipoyllysine-residue succinyltransferase component of2-oxoglutarate dehydrogenase complex, mitochondrial precursor(Dihydrolipoamide succinyltransferase component of 2-oxoglutaratedehydrogenase complex) (E2) (E2K); (1682:) dihydroorotate dehydrogenaseisoform 1 precursor [Homo sapiens]; (1683:) dihydroorotate dehydrogenaseisoform 2 precursor [Homo sapiens]; (1684:) Dihydroorotatedehydrogenase, mitochondrial precursor (Dihydroorotate oxidase)(DHOdehase); (1685:) Dihydropteridine reductase (HDHPR) (Quinoiddihydropteridine reductase); (1686:) dihydropyrimidine dehydrogenase[Homo sapiens]; (1687:) Dihydropyrimidine dehydrogenase [NADP+]precursor (DPD) (DHPDHase) (Dihydrouracil dehydrogenase) (Dihydrothyminedehydrogenase); (1688:) dihydropyrimidine dehydrogenase; (1689:)dimerization cofactor of hepatocyte nuclear factor 1 (HNF1) from muscle[Homo sapiens]; (1690:) dimethylaniline monooxygenase (N-oxide-forming)(EC 1.14.13.8), hepatic 2-human; (1691:) Dimethylaniline monooxygenase[N-oxide-forming] 5 (Hepaticflavin-containing monooxygenase 5) (FMO 5)(Dimethylaniline oxidase 5); (1692:) dimethylargininedimethylaminohydrolase 1 [Homo sapiens]; (1693:) dimethylargininedimethylaminohydrolase 2 [Homo sapiens]; (1694:) dimethylglycinedehydrogenase precursor [Homo sapiens]; (1695:) DIP2 disco-interactingprotein 2 homolog B [Homo sapiens]; (1696:) DIP2 disco-interactingprotein 2 homolog C (Drosophila) [Homo sapiens]; (1697:) DIP2disco-interacting protein 2 homolog C [Homo sapiens]; (1698:) DIP2Bprotein [Homo sapiens]; (1699:) DIP2C protein [Homo sapiens]; (1700:)DIP2-like protein isoform a [Homo sapiens]; (1701:) dipeptidase 1(renal) [Homo sapiens]; (1702:) Dipeptidase 1 precursor (Microsomaldipeptidase) (Renal dipeptidase) (hRDP) (Dehydropeptidase-1); (1703:)Dipeptidase 2 precursor; (1704:) Dipeptidase 3 precursor; (1705:)dipeptidyl peptidase 7 preproprotein [Homo sapiens]; (1706:) Dipeptidylpeptidase 8 (Dipeptidyl peptidase VIII) (DP8) (Prolyl dipeptidase DPP8)(Dipeptidyl peptidase IV-related protein 1) (DPRP-1); (1707:) dipeptidylpeptidase 8 [Homo sapiens]; (1708:) dipeptidyl peptidase 8 isoform 1[Homo sapiens]; (1709:) dipeptidyl peptidase 8 isoform 2 [Homo sapiens];(1710:) dipeptidyl peptidase 8 isoform 3 [Homo sapiens]; (1711:)dipeptidyl peptidase 8 isoform 4 [Homo sapiens]; (1712:) Dipeptidylpeptidase 9 (Dipeptidyl peptidase IX) (DP9) (Dipeptidylpeptidase-likeprotein 9) (DPLP9) (Dipeptidyl peptidase IV-related protein 2) (DPRP-2);(1713:) dipeptidyl peptidase III [Homo sapiens]; (1714:)dipeptidylpeptidase 9 [Homo sapiens]; (1715:) dipeptidylpeptidase IV[Homo sapiens]; (1716:) Diphosphoinositol polyphosphate phosphohydrolase1 (DIPP-1) (Diadenosine 5′,5″-P1,P6-hexaphosphate hydrolase 1)(Nucleosidediphosphate-linked moiety X motif 3) (Nudix motif 3); (1717:)Diphosphoinositol polyphosphate phosphohydrolase 2 (DIPP-2) (Diadenosine5′,5″-P1,P6-hexaphosphate hydrolase 2) (Nucleosidediphosphate-linkedmoiety X motif 4) (Nudix motif 4); (1718:) Diphosphoinositolpolyphosphate phosphohydrolase 3 alpha (DIPP-3alpha) (DIPP3 alpha)(hDIPP3alpha) (Diadenosine-5′,5′″-P1,P6-hexaphosphate hydrolase 3 alpha)(Nucleosidediphosphate-linked moiety X motif 10) (Nudix motif 10)(hAps2); (1719:) Diphosphoinositol polyphosphate phosphohydrolase 3 beta(DIPP-3beta) (DIPP3 beta) (hDIPP3beta)(Diadenosine-5′,5′″-P1,P6-hexaphosphate hydrolase 3 beta)(Nucleosidediphosphate-linked moiety X motif 11) (Nudix motif 11)(hAps1); (1720:) diphosphomevalonate decarboxylase [Homo sapiens];(1721:) Discoidin domain-containing receptor 2 precursor (Discoidindomain receptor 2) (Receptor protein-tyrosine kinase TKT)(Tyrosine-protein kinase TYRO 10) (Neurotrophic tyrosine kinase,receptor-related 3) (CD167b antigen); (1722:) Disco-interacting protein2 homolog A; (1723:) Disco-interacting protein 2 homolog C; (1724:) DLST[Homo sapiens]; (1725:) DNA (cytosine-5-)-methyltransferase 1 [Homosapiens]; (1726:) DNA cytosine methyltransferase 3 alpha isoform a [Homosapiens]; (1727:) DNA cytosine methyltransferase 3 alpha isoform b [Homosapiens]; (1728:) DNA cytosine methyltransferase 3 alpha isoform c [Homosapiens]; (1729:) DNA cytosine-5 methyltransferase 3 beta isoform 1[Homo sapiens]; (1730:) DNA cytosine-5 methyltransferase 3 beta isoform2 [Homo sapiens]; (1731:) DNA cytosine-5 methyltransferase 3 betaisoform 3 [Homo sapiens]; (1732:) DNA cytosine-5 methyltransferase 3beta isoform 6 [Homo sapiens]; (1733:) DNA dC->dU-editing enzymeAPOBEC-3F (Apolipoprotein B mRNA-editing enzyme catalyticpolypeptide-like 3F); (1734:) DNA dC->dU-editing enzyme APOBEC-3G(APOBEC-related cytidine deaminase) (ARCD) (APOBEC-related protein)(ARP-9) (CEM15) (CEM-15); (1735:) DNA directed RNA polymerase IIpolypeptide A [Homo sapiens]; (1736:) DNA directed RNA polymerase IIpolypeptide B [Homo sapiens]; (1737:) DNA fragmentation factor subunitbeta (DNA fragmentation factor 40 kDa subunit) (DFF-40)(Caspase-activated deoxyribonuclease) (Caspase-activated DNase) (CAD)(Caspase-activated nuclease) (CPAN); (1738:) DNA helicase II, HDHII=ATP-dependent DNA unwinding enzyme/Ku autoantigen large subunit{N-terminal} [human, HeLa cells, Peptide Partial, 19 aa]; (1739:) DNAligase 3 (DNA ligase III) (Polydeoxyribonucleotide synthase [ATP] 3);(1740:) DNA ligase 4 (DNA ligase IV) (Polydeoxyribonucleotide synthase[ATP]-4); (1741:) DNA ligase I [Homo sapiens]; (1742:) DNA ligase III[Homo sapiens]; (1743:) DNA ligase IV [Homo sapiens]; (1744:) DNAmismatch repair protein [Homo sapiens]; (1745:) DNA mismatch repairprotein homolog [Homo sapiens]; (1746:) DNA mismatch repair protein Mlh1(MutL protein homolog 1); (1747:) DNA mismatch repair protein Mlh3 (MutLprotein homolog 3); (1748:) DNA mismatch repair protein MLH3 [Homosapiens]; (1749:) DNA mismatch repair protein; (1750:) DNAnucleotidylexotransferase (Terminal addition enzyme) (Terminaldeoxynucleotidyl transferase) (Terminal transferase); (1751:) DNApolymerase beta; (1752:) DNA polymerase beta2 [Homo sapiens]; (1753:)DNA polymerase epsilon, catalytic subunit A (DNA polymerase II subunitA); (1754:) DNA polymerase lambda (Pol Lambda) (DNA polymerase kappa)(DNA polymerase beta-2) (Pol beta2); (1755:) DNA polymerase subunitalpha B (DNA polymerase alpha 70 kDa subunit); (1756:) DNA polymerasesubunit gamma 2, mitochondrial precursor (Mitochondrial DNA polymeraseaccessory subunit) (PoIG-beta) (MtPoIB) (DNA polymerase gamma accessory55 kDa subunit) (p55); (1757:) DNA polymerase theta [Homo sapiens];(1758:) DNA primase large subunit, 58 kDa [Homo sapiens]; (1759:) DNAprimase small subunit, 49 kDa [Homo sapiens]; (1760:) DNA repair enzyme;(1761:) DNA replication licensing factor MCM6 (p105MCM); (1762:) DNAtopoisomerase 1 (DNA topoisomerase I); (1763:) DNA topoisomerase 2-alpha(DNA topoisomerase II, alpha isozyme); (1764:) DNA topoisomerase I [Homosapiens]; (1765:) DNA topoisomerase 1, mitochondrial precursor (TOP1mt);(1766:) DNA topoisomerase II [Homo sapiens]; (1767:) DNA topoisomeraseII, alpha isozyme [Homo sapiens]; (1768:) DNA topoisomerase II, betaisozyme [Homo sapiens]; (1769:) DNA-(apurinic or apyrimidinic site)lyase (AP endonuclease 1) (APEX nuclease) (APEN) (REF-1 protein);(1770:) DNA-3-methyladenine glycosylase (3-methyladenine DNAglycosidase) (ADPG) (3-alkyladenine DNA glycosylase) (N-methylpurine-DNA glycosylase); (1771:) DNA-binding protein [Homo sapiens];(1772:) DNA-dependent protein kinase catalytic subunit (DNA-PK catalyticsubunit) (DNA-PKcs) (DNPK1) (p460); (1773:) DNA-directed RNA polymeraseII 19 kDa polypeptide (RPB7); (1774:) DNA-directed RNA polymerase IIIlargest subunit (RPC155) (RPC1); (1775:) DNA-directed RNA polymerase IIIsubunit C (DNA-directed III 62 kDa polypeptide) (RNA polymerase III C62subunit) (RPC3); (1776:) DnaJ (Hsp40) homolog, subfamily B, member 6isoform a [Homo sapiens]; (1777:) DnaJ (Hsp40) homolog, subfamily B,member 6 isoform b [Homo sapiens]; (1778:) docking protein 1 [Homosapiens]; (1779:) dodecenoyl-CoA delta-isomerase [Homo sapiens]; (1780:)dodecenoyl-Coenzyme A delta isomerase precursor [Homo sapiens]; (1781:)dolichol monophosphate mannose synthase [Homo sapiens]; (1782:)Dolichol-phosphate mannosyltransferase (Dolichol-phosphatemannosesynthase) (Dolichyl-phosphate beta-D-mannosyltransferase)(Mannose-P-dolichol synthase) (MPD synthase) (DPM synthase); (1783:)Dolichyl-diphosphooligosaccharide—protein glycosyltransferase 48 kDasubunit precursor (Oligosaccharyl transferase 48 kDa subunit) (DDOST 48kDa subunit); (1784:) Dolichyl-diphosphooligosaccharide—proteinglycosyltransferase 63 kDa subunit precursor (Ribophorin II) (RPN-II)(RIBIIR); (1785:) Dolichyl-diphosphooligosaccharide—proteinglycosyltransferase 67 kDa subunit precursor (Ribophorin I) (RPN-I);(1786:) Dolichyl-diphosphooligosaccharide—protein glycosyltransferasesubunit DAD1 (Oligosaccharyl transferase subunit DAD1) (Defender againstcell death 1) (DAD-1); (1787:) Dolichyl-diphosphooligosaccharide—proteinglycosyltransferase subunit STT3A (Oligosaccharyl transferase subunitSTT3A) (STT3-A) (B5) (Integral membrane protein 1) (TMC); (1788:)Dolichyl-diphosphooligosaccharide—protein glycosyltransferase subunitSTT3B (Oligosaccharyl transferase subunit STT3B) (STT3-B) (Source ofimmunodominant MHC-associated peptides homolog); (1789:)dolichyl-phosphate mannosyltransferase polypeptide 1 [Homo sapiens];(1790:) dolichyl-phosphate mannosyltransferase polypeptide 2, regulatorysubunit [Homo sapiens]; (1791:) dolichyl-phosphate mannosyltransferasepolypeptide 3 isoform 1 [Homo sapiens]; (1792:) dolichyl-phosphatemannosyltransferase polypeptide 3 isoform 2 [Homo sapiens]; (1793:)DOLPP1 protein [Homo sapiens]; (1794:) dopa decarboxylase (aromaticL-amino acid decarboxylase) [Homo sapiens]; (1795:) dopachrometautomerase (dopachrome delta-isomerase, tyrosine-related protein 2)[Homo sapiens]; (1796:) Dopamine beta-hydroxylase precursor (Dopaminebeta-monooxygenase); (1797:) dopamine beta-hydroxylase precursor [Homosapiens]; (1798:) double-stranded RNA adenosine deaminase; (1799:)Double-stranded RNA-specific adenosine deaminase (DRADA) (136 kDadouble-stranded RNA-binding protein) (P136) (K88DSRBP)(Interferon-inducible protein 4) (IFI-4 protein); (1800:)Double-stranded RNA-specific editase 1 (dsRNA adenosine deaminase)(RNA-editing deaminase 1) (RNA-editing enzyme 1); (1801:)Double-stranded RNA-specific editase B2 (dsRNA adenosine deaminase B2)(RNA-dependent adenosine deaminase 3) (RNA-editing deaminase 2)(RNA-editing enzyme 2); (1802:) Drug-Protein Interactions:) Structure OfSulfonamide Drug Complexed With Human Carbonic Anhydrase I; (1803:)dsRNA adenosine deaminase DRADA2a [Homo sapiens]; (1804:) dsRNAadenosine deaminase DRADA2b [Homo sapiens]; (1805:) dsRNA adenosinedeaminase DRADA2c [Homo sapiens]; (1806:) Dual 3′,5′-cyclic-AMP and -GMPphosphodiesterase 11A (cAMP and cGMP phosphodiesterase 11A); (1807:)Dual oxidase 1 precursor (NADPH thyroid oxidase 1) (Thyroid oxidase 1)(Large NOX 1) (Long NOX 1); (1808:) Dual oxidase 2 precursor (NADPHoxidase/peroxidase DUOX2) (NADPH thyroid oxidase 2) (Thyroid oxidase 2)(NADH/NADPH thyroid oxidase p138-tox) (p138 thyroid oxidase) (Large NOX2) (Long NOX 2); (1809:) Dual specificity mitogen-activated proteinkinase kinase 1 (MAPkinase kinase 1) (MAPKK 1) (ERK activator kinase 1)(MAPK/ERK kinase 1) (MEK1); (1810:) Dual specificity mitogen-activatedprotein kinase kinase 3 (MAPkinase kinase 3) (MAPKK 3) (MAPK/ERK kinase3); (1811:) Dual specificity mitogen-activated protein kinase kinase 6(MAPkinase kinase 6) (MAPKK 6) (MAPK/ERK kinase 6) (SAPKK3); (1812:)Dual specificity protein phosphatase 18 (Low molecular weight dualspecificity phosphatase 20); (1813:) Dual specificity proteinphosphatase 23 (Low molecular mass dual specificity phosphatase 3)(LDP-3) (VH1-like phosphatase Z); (1814:) Dual specificitytestis-specific protein kinase 1 (Testicular protein kinase 1); (1815:)Dual specificity testis-specific protein kinase 2 (Testicular proteinkinase 2); (1816:) Dual specificity tyrosine-phosphorylation-regulatedkinase 1A (Protein kinase minibrain homolog) (MNBH) (HP86) (Dualspecificity YAK1-related kinase); (1817:) Dual specificitytyrosine-phosphorylation-regulated kinase 1B (Mirk protein kinase)(Minibrain-related kinase); (1818:) Dual specificitytyrosine-phosphorylation-regulated kinase 2; (1819:) Duffyantigen/chemokine receptor (Fy glycoprotein) (GpFy) (Glycoprotein D)(Plasmodium vivax receptor) (CD234 antigen); (1820:) dUTPpyrophosphatase isoform 1 precursor [Homo sapiens]; (1821:) dUTPpyrophosphatase isoform 2 [Homo sapiens]; (1822:) dUTP pyrophosphataseisoform 3 [Homo sapiens]; (1823:) dUTP pyrophosphatase; (1824:) dynamin1 isoform 1 [Homo sapiens]; (1825:) dynamin 1 isoform 2 [Homo sapiens];(1826:) Dynamin-1-like protein (Dynamin-like protein) (Dnm1p/Vps1p-likeprotein) (DVLP) (Dynamin family member proline-rich carboxyl-terminaldomain less) (Dymple) (Dynamin-related protein 1) (Dynamin-like protein4) (Dynamin-like protein IV) (HdynIV); (1827:) dynein light chain 1[Homo sapiens]; (1828:) dystonin isoform 1 [Homo sapiens]; (1829:)dystonin isoform 1e precursor [Homo sapiens]; (1830:) dystonin isoform1eA precursor [Homo sapiens]; (1831:) dystonin isoform 1eB precursor[Homo sapiens]; (1832:) E-1 enzyme [Homo sapiens]; (1833:) E1A bindingprotein p300 [Homo sapiens]; (1834:) E1A-associated protein p300;(1835:) E2 protein [Homo sapiens]; (1836:) E2 ubiquitin-conjugatingenzyme [Homo sapiens]; (1837:) E2F transcription factor 2 [Homosapiens]; (1838:) E3 ubiquitin ligase IBRDC2 (IBR domain-containingprotein 2) (p53-inducible RING finger protein); (1839:) E3 ubiquitinligase TRIAD3 (Ubiquitin-conjugating enzyme7-interacting protein 1)(Zinc finger protein inhibiting NF-kappa-B) (Triad domain-containingprotein 3); (1840:) E3 ubiquitin protein ligase TRAF7 (TNFreceptor-associated factor 7) (RING finger and WD repeat domainprotein 1) (RING finger protein 119); (1841:) E3 ubiquitin-proteinligase CBL (Signal transduction protein CBL) (Proto-oncogene c-CBL)(Casitas B-lineage lymphoma proto-oncogene) (RING finger protein 55);(1842:) E3 ubiquitin-protein ligase CBL-B (Signal transduction proteinCBL-B) (SH3-binding protein CBL-B) (Casitas B-lineage lymphomaproto-oncogene b) (RING finger protein 56); (1843:) E3 ubiquitin-proteinligase HECTD1 (HECT domain-containing protein1) (E3 ligase for inhibinreceptor) (EULIR); (1844:) E3 ubiquitin-protein ligase NEDD4; (1845:) E3ubiquitin-protein ligase NEDD4-like protein (Nedd-4-2) (NEDD4.2);(1846:) early growth response 1 [Homo sapiens]; (1847:) EBV-inducedG-protein coupled receptor 2 (EBI2); (1848:) ECE-1 [Homo sapiens];(1849:) ectonucleoside triphosphate diphosphohydrolase 2 isoform 1 [Homosapiens]; (1850:) ectonucleoside triphosphate diphosphohydrolase 2isoform 2 [Homo sapiens]; (1851:) “Ectonucleotidepyrophosphatase/phosphodiesterase 1 (E-NPP 1) (PhosphodiesteraseI/nucleotide pyrophosphatase 1) (Plasma-cell membrane glycoprotein PC-1)[Includes:) Alkaline phosphodiesterase I; Nucleotide pyrophosphatase(NPPase)].”; (1852:) Ectonucleotide pyrophosphatase/phosphodiesterase 6precursor (E-NPP6) (NPP-6) [Contains:) Ectonucleotidepyrophosphatase/phosphodiesterase 6 soluble form]; (1853:)ectonucleotide pyrophosphatase/phosphodiesterase 7 [Homo sapiens];(1854:) Ectonucleotide pyrophosphatase/phosphodiesterase 7 precursor(E-NPP7) (NPP-7) (Alkaline sphingomyelin phosphodiesterase) (Intestinalalkaline sphingomyelinase) (Alk-SMase); (1855:) EGF, latrophilin andseven transmembrane domain-containing protein1 precursor(EGF-TM7-latrophilin-related protein) (ETL protein); (1856:) EGF-likemodule-containing mucin-like hormone receptor-like 1 precursor (Cellsurface glycoprotein EMR1) (EMR1 hormone receptor); (1857:) EGF-likemodule-containing mucin-like hormone receptor-like 2precursor (EGF-likemodule EMR2) (CD312 antigen); (1858:) EGF-like module-containingmucin-like hormone receptor-like 3precursor (EGF-like module-containingmucin-like receptor EMR3); (1859:) EGF-like module-containing mucin-likehormone receptor-like 4precursor (G-protein coupled receptor 127);(1860:) EGL nine (C. elegans) homolog 2 isoform 1 [Homo sapiens];(1861:) EGL nine (C. elegans) homolog 2 isoform 2 [Homo sapiens];(1862:) EGL nine (C. elegans) homolog 2 isoform 3 [Homo sapiens];(1863:) Egl nine homolog 1 (Hypoxia-inducible factor prolyl hydroxylase2) (HIF-prolyl hydroxylase 2) (HIF-PH2) (HPH-2) (Prolyl hydroxylasedomain-containing protein 2) (PHD2) (SM-20); (1864:) Egl nine homolog 3(Hypoxia-inducible factor prolyl hydroxylase 3) (HIF-prolyl hydroxylase3) (HIF-PH3) (HPH-1) (Prolyl hydroxylase domain-containing protein 3)(PHD3); (1865:) elastase 1, pancreatic [Homo sapiens]; (1866:) elastase2, neutrophil preproprotein [Homo sapiens]; (1867:) elastase isozyme 4,HSE I-4 [human, sputum, Peptide Partial, 21aa]; (1868:) ELAV-like 1[Homo sapiens]; (1869:) Electrogenic sodium bicarbonate cotransporter 1(Sodium bicarbonate cotransporter) (Na(+)/HCO3(−) cotransporter) (Solutecarrier family 4 member 4) (kNBC1); (1870:) Elongation factor 2 kinase(eEF-2 kinase) (eEF-2K) (Calcium/calmodulin-dependent eukaryoticelongation factor 2kinase); (1871:) elongin B [Homo sapiens]; (1872:)elongin B isoform a [Homo sapiens]; (1873:) elongin B isoform b [Homosapiens]; (1874:) elongin C [Homo sapiens]; (1875:)endo-beta-N-acetylglucosaminidase [Homo sapiens]; (1876:) endonucleaseIII [Homo sapiens]; (1877:) Endonuclease III-like protein 1; (1878:)Endonuclease VIII-like 2 (Nei-like 2) (DNA glycosylase/AP lyase Nei12)(DNA-(apurinic or apyrimidinic site) lyase Nei12) (NEH2); (1879:)endopeptidase La homolog (EC 3.4.21.-) precursor, mitochondrial (version2)-human; (1880:) endoplasmic reticulum alpha-mannosidase I [Homosapiens]; (1881:) Endoplasmic reticulum mannosyl-oligosaccharide1,2-alpha-mannosidase (ER alpha-1,2-mannosidase) (Mannosidase alphaclass 1B member 1) (Man9GlcNAc2-specific-processing alpha-mannosidase);(1882:) endothelial cell growth factor 1 (platelet-derived) [Homosapiens]; (1883:) Endothelial cells scavenger receptor precursor (AcetylLDL receptor) (Scavenger receptor class F member 1); (1884:) Endotheliallipase precursor (Endothelial cell-derived lipase) (EDL) (EL); (1885:)Endothelial protein C receptor precursor (Endothelial cell protein Creceptor) (Activated protein C receptor) (APC receptor) (CD201 antigen);(1886:) endothelin 1 [Homo sapiens]; (1887:) endothelin 3 isoform 1preproprotein [Homo sapiens]; (1888:) endothelin 3 isoform 2preproprotein [Homo sapiens]; (1889:) endothelin 3 isoform 3preproprotein [Homo sapiens]; (1890:) Endothelin B receptor precursor(ET-B) (Endothelin receptor Non-selective type); (1891:) Endothelin Breceptor-like protein 2 precursor (ETBR-LP-2) (G-protein coupledreceptor 37-like 1); (1892:) endothelin converting enzyme [Homosapiens]; (1893:) endothelin converting enzyme 1 [Homo sapiens]; (1894:)endothelin converting enzyme 1 isoform 1c [Homo sapiens]; (1895:)endothelin converting enzyme 2 isoform A [Homo sapiens]; (1896:)endothelin converting enzyme 2 isoform B [Homo sapiens]; (1897:)endothelin converting enzyme-1 [Homo sapiens]; (1898:) endothelinconverting enzyme-2A [Homo sapiens]; (1899:) endothelin convertingenzyme-2B [Homo sapiens]; (1900:) endothelin converting enzyme-like 1[Homo sapiens]; (1901:) endothelin receptor type A [Homo sapiens];(1902:) endothelin receptor type β isoform 1 [Homo sapiens]; (1903:)endothelin receptor type β isoform 2 [Homo sapiens]; (1904:)Endothelin-1 receptor precursor (Endothelin A receptor) (ET-A) (hET-AR)(ETA-R); (1905:) endothelin-converting enzyme [Homo sapiens]; (1906:)Endothelin-converting enzyme 1 (ECE-1); (1907:) Endothelin-convertingenzyme 2 (ECE-2); (1908:) endothelin-converting enzyme 2B [Homosapiens]; (1909:) endothelin-converting enzyme, isoform ECE-1a [Homosapiens]; (1910:) endothelin-converting enzyme, isoform ECE-1b [Homosapiens]; (1911:) endothelin-converting enzyme; (1912:)endothelin-converting enzyme-1c [Homo sapiens]; (1913:)endothelin-converting enzyme-2C [Homo sapiens]; (1914:)Endothelin-converting enzyme-like 1 (Xce protein); (1915:)endothelin-converting-enzyme 1 [Homo sapiens]; (1916:)endotheline-converting enzyme ECEL1 [Homo sapiens]; (1917:) enolase 1[Homo sapiens]; (1918:) enolase 2 [Homo sapiens]; (1919:) enolase 3[Homo sapiens]; (1920:) enoyl-CoA hydratase:) 3-hydroxyacyl-CoAdehydrogenase; (1921:) enoyl-Coenzyme A, hydratase/3-hydroxyacylCoenzyme A dehydrogenase[Homo sapiens]; (1922:) enterocytedifferentiation associated factor EDAF-1 [Homo sapiens]; (1923:)enterokinase precursor [Homo sapiens]; (1924:) enyol-CoA:)hydratase/3-hydroxyacyl-CoA dehydrogenase; (1925:) eosinophil serineprotease [Homo sapiens]; (1926:) eosinophil serine protease 1 splicingvariant [Homo sapiens]; (1927:) ephrin receptor EphB2 isoform 1precursor [Homo sapiens]; (1928:) ephrin receptor EphB2 isoform 2precursor [Homo sapiens]; (1929:) Ephrin type-A receptor 1 precursor(Tyrosine-protein kinase receptor EPH); (1930:) Ephrin type-A receptor10 precursor; (1931:) Ephrin type-A receptor 2 precursor(Tyrosine-protein kinase receptor ECK) (Epithelial cell kinase); (1932:)

Ephrin type-A receptor 3 precursor (Tyrosine-protein kinase receptorETK1) (HEK) (HEK4); (1933:) Ephrin type-A receptor 4 precursor(Tyrosine-protein kinase receptor SEK) (Receptor protein-tyrosine kinaseHEK8); (1934:) Ephrin type-A receptor 5 precursor (Tyrosine-proteinkinase receptor EHK-1) (EPH homology kinase 1) (Receptorprotein-tyrosine kinase HEK7); (1935:) Ephrin type-A receptor 6precursor (Tyrosine-protein kinase receptor EHK-2) (EPH homology kinase2); (1936:) Ephrin type-A receptor 7 precursor (Tyrosine-protein kinasereceptor EHK-3) (EPH homology kinase 3) (Receptor protein-tyrosinekinase HEK11); (1937:) Ephrin type-A receptor 8 precursor(Tyrosine-protein kinase receptor EEK) (EPH- and ELK-related kinase)(HEK3); (1938:) Ephrin type-B receptor 1 precursor (Tyrosine-proteinkinase receptor EPH-2) (NET) (HEK6) (ELK); (1939:) Ephrin type-Breceptor 2 precursor (Tyrosine-protein kinase receptor EPH-3) (DRT)(Receptor protein-tyrosine kinase HEK5) (ERK) (NY-REN-47 antigen);(1940:) Ephrin type-B receptor 3 precursor (Tyrosine-protein kinasereceptor HEK-2); (1941:) Ephrin type-B receptor 4 precursor(Tyrosine-protein kinase receptor HTK); (1942:) Ephrin type-B receptor 6precursor (Tyrosine-protein kinase-defective receptor EPH-6) (HEP);(1943:) epidermal growth factor (beta-urogastrone) [Homo sapiens];(1944:) epidermal growth factor receptor isoform a [Homo sapiens];(1945:) epidermal growth factor receptor isoform b [Homo sapiens];(1946:) epidermal growth factor receptor isoform c [Homo sapiens];(1947:) epidermal growth factor receptor isoform d [Homo sapiens];(1948:) epidermal growth factor receptor pathway substrate 15 [Homosapiens]; (1949:) Epidermal growth factor receptor precursor (Receptortyrosine-protein kinase ErbB-1); (1950:) Epithelial discoidindomain-containing receptor 1 precursor (Epithelial discoidin domainreceptor 1) (Tyrosine kinase DDR) (Discoidin receptor tyrosine kinase)(Tyrosine-protein kinase CAK) (Cell adhesion kinase) (TRK E)(Protein-tyrosine kinase RTK 6) (HGK2) (CD167a antigen); (1951:) Epoxidehydrolase 1 (Microsomal epoxide hydrolase) (Epoxidehydratase); (1952:)Epoxide hydrolase 2 (Soluble epoxide hydrolase) (SEH) (Epoxidehydratase)(Cytosolic epoxide hydrolase) (CEH); (1953:) epoxide hydrolase 2,cytoplasmic [Homo sapiens]; (1954:) epsilon isoform of regulatorysubunit B56, protein phosphatase 2A[Homo sapiens]; (1955:)epsilon-trimethyllysine 2-oxoglutarate dioxygenase [Homo sapiens];(1956:) ER lumen protein retaining receptor 1 (KDEL receptor 1) (KDELendoplasmic reticulum protein retention receptor 1) (PutativeMAPK-activating protein PM23); (1957:) ER lumen protein retainingreceptor 2 (KDEL receptor 2) (KDEL endoplasmic reticulum proteinretention receptor 2) (ERD2-like protein 1) (ELP-1); (1958:) ER lumenprotein retaining receptor 3 (KDEL receptor 3) (KDEL endoplasmicreticulum protein retention receptor 3); (1959:) ERO1-like protein alphaprecursor (ERO1-L alpha) (Oxidoreductin-1-L alpha) (Endoplasmicoxidoreductin-1-like protein) (ERO1-L); (1960:) ERO1-like protein betaprecursor (ERO1-L beta) (Oxidoreductin-1-L beta) (Endoplasmicoxidoreductin-1-like protein B); (1961:) erythrocyte acylphosphatase 1isoform a [Homo sapiens]; (1962:) erythrocyte acylphosphatase 1 isoformb [Homo sapiens]; (1963:) erythrocyte adenosine monophosphate deaminaseisoform 1A [Homo sapiens]; (1964:) erythrocyte adenosine monophosphatedeaminase isoform 1B [Homo sapiens]; (1965:) erythrocyte adenosinemonophosphate deaminase isoform 1C [Homo sapiens]; (1966:)Erythropoietin receptor precursor (EPO-R); (1967:) estradiol 17beta-dehydrogenase 8 [Homo sapiens]; (1968:) Estradiol17-beta-dehydrogenase 1 (17-beta-hydroxysteroid dehydrogenase type 1)(17-beta-HSD1) (Placental 17-beta-hydroxysteroid dehydrogenase) (20alpha-hydroxysteroid dehydrogenase) (20-alpha-HSD) (E2DH); (1969:)Estradiol 17-beta-dehydrogenase 12 (17-beta-HSD 12)(17-beta-hydroxysteroid dehydrogenase 12) (3-ketoacyl-CoA reductase)(KAR); (1970:) Estradiol 17-beta-dehydrogenase 2 (17-beta-HSD 2)(Microsomal 17-beta-hydroxysteroid dehydrogenase) (20alpha-hydroxysteroid dehydrogenase) (20-alpha-HSD) (E2DH); (1971:)Estrogen receptor (ER) (Estradiol receptor) (ER-alpha); (1972:) Estrogenreceptor beta (ER-beta); (1973:) estrogen-related receptor alpha [Homosapiens]; (1974:) Estrogen-related receptor gamma (Estrogenreceptor-related protein3) (ERR gamma-2); (1975:) ethanolamine kinase 1isoform A [Homo sapiens]; (1976:) ethanolamine kinase 1 isoform B [Homosapiens]; (1977:) ets variant gene 6 [Homo sapiens]; (1978:) Eukaryotictranslation initiation factor 2-alpha kinase 1 (Heme-regulatedeukaryotic initiation factor eIF-2-alpha kinase) (Heme-regulatedinhibitor) (Heme-controlled repressor) (HCR) (Hemin-sensitive initiationfactor 2-alpha kinase); (1979:) eukaryotic translation initiation factor2-alpha kinase 2 [Homo sapiens]; (1980:) Eukaryotic translationinitiation factor 2-alpha kinase 3 precursor (PRKR-like endoplasmicreticulum kinase) (Pancreatic eIF2-alpha kinase) (HsPEK); (1981:)Eukaryotic translation initiation factor 4 gamma 2 (eIF-4-gamma 2)(eIF-4G 2) (eIF4G 2) (p97) (Death-associated protein 5) (DAP-5); (1982:)evolutionarily related interleukin-1 beta converting enzyme [Homosapiens]; (1983:) Exostosin-like 2(Glucuronyl-galactosyl-proteoglycan-4-alpha-N-acetylglucosaminyltransferase)(Alpha-1,4-N-acetylhexosaminyltransferase EXTL2) (Alpha-GalNAcTEXTL2)(EXT-related protein 2); (1984:) Extracellular calcium-sensing receptorprecursor (CaSR) (Parathyroid Cell calcium-sensing receptor); (1985:)FAD synthetase isoform 1 [Homo sapiens]; (1986:) FAD1 flavin adeninedinucleotide synthetase homolog (S. cerevisiae)[Homo sapiens]; (1987:)FADD-homologous ICE/CED-3-like protease [Homo sapiens]; (1988:)FAD-synthetase (PP591) [Homo sapiens]; (1989:) FAD-synthetase [Homosapiens]; (1990:) FAM80B protein [Homo sapiens]; (1991:) Family withsequence similarity 80, member A [Homo sapiens]; (1992:) Family withsequence similarity 80, member B [Homo sapiens]; (1993:) Fanconi anemiacomplementation group D2 isoform a [Homo sapiens]; (1994:) Fanconianemia complementation group D2 isoform b [Homo sapiens]; (1995:)Fanconi anemia group D2 protein (Protein FACD2); (1996:) Fanconi anemia,complementation group G [Homo sapiens]; (1997:) Far upstreamelement-binding protein 2 (FUSE-binding protein 2) (KH type-splicingregulatory protein) (KSRP) (p75); (1998:) farnesyl diphosphate synthase[Homo sapiens]; (1999:) farnesylated-proteins converting enzyme 1 [Homosapiens]; (2000:) farnesylated-proteins converting enzyme 2 [Homosapiens]; (2001:) farnesyl-diphosphate farnesyltransferase 1 [Homosapiens]; (2002:) Fas-associated death domain proteininterleukin-1b-converting enzyme 2 [Homo sapiens]; (2003:)Fas-associated via death domain [Homo sapiens]; (2004:) fatty acid amidehydrolase [Homo sapiens]; (2005:) fatty acid CoA ligase-like AMP-bindingenzyme [Homo sapiens]; (2006:) fatty acid coenzyme A ligase 5 [Homosapiens]; (2007:) fatty acid desaturase 2 [Homo sapiens]; (2008:) fattyacid omega-hydroxylase (cytochrome P450 4A); (2009:) fatty acid synthase[Homo sapiens]; (2010:) fatty-acid-Coenzyme A ligase, long-chain 5 [Homosapiens]; (2011:) FBP2 [Homo sapiens]; (2012:) Fc receptor-like protein2 precursor (SH2 domain-containing phosphatase anchor protein 1) (Fcreceptor homolog 2) (FcRH2) (Immunoglobulin receptortranslocation-associated 4 protein); (2013:) Fc receptor-like protein 5precursor (Immunoglobulin receptor translocation-associated gene 2protein) (BXMAS1) (CD307 antigen); (2014:) Feline leukemia virussubgroup C receptor-related protein 1 (Feline leukemia virus subgroup Creceptor) (hFLVCR); (2015:) ferredoxin 1 precursor [Homo sapiens];(2016:) ferredoxin reductase isoform 1 precursor [Homo sapiens]; (2017:)ferredoxin reductase isoform 2 precursor [Homo sapiens]; (2018:)Ferrochelatase (protoporphyria) [Homo sapiens]; (2019:) ferrochelatase[Homo sapiens]; (2020:) ferrochelatase isoform a precursor [Homosapiens]; (2021:) ferrochelatase isoform b precursor [Homo sapiens];(2022:) ferrochelatase precursor [Homo sapiens]; (2023:) Ferrochelatase,mitochondrial precursor (Protoheme ferro-lyase) (Heme synthetase);(2024:) fibrinogen, alpha polypeptide isoform alpha preproprotein [Homosapiens]; (2025:) fibrinogen, alpha polypeptide isoform alpha-Epreproprotein [Homo sapiens]; (2026:) fibroblast activation protein,alpha subunit [Homo sapiens]; (2027:) fibroblast growth factor 23precursor [Homo sapiens]; (2028:) Fibroblast growth factor receptor 2precursor (FGFR-2) (Keratinocyte growth factor receptor 2) (CD332antigen); (2029:) Fibroblast growth factor receptor 3 precursor (FGFR-3)(CD333antigen); (2030:) Fibroblast growth factor receptor 4 precursor(FGFR-4) (CD334antigen); (2031:) Fibroblast growth factor receptor-like1 precursor (FGF receptor-like protein 1) (Fibroblast growth factorreceptor 5) (FGFR-like protein) (FGF homologous factor receptor);(2032:) fibronectin 1 isoform 1 preproprotein [Homo sapiens]; (2033:)fibronectin 1 isoform 2 preproprotein [Homo sapiens]; (2034:)fibronectin 1 isoform 3 preproprotein [Homo sapiens]; (2035:)fibronectin 1 isoform 4 preproprotein [Homo sapiens]; (2036:)fibronectin 1 isoform 5 preproprotein [Homo sapiens]; (2037:)fibronectin 1 isoform 6 preproprotein [Homo sapiens]; (2038:)fibronectin 1 isoform 7 preproprotein [Homo sapiens]; (2039:) Fk506 AndRapamycin-Binding Protein (Fkbp12) (Nmr, 20 Structures); (2040:) Fk506And Rapamycin-Binding Protein (Fkbp12) (Nmr, Minimized Average StructureExcluding Electrostatic Interactions); (2041:) Fk506 AndRapamycin-Binding Protein (Fkbp12) (Nmr, Minimized Average Structure);(2042:) FK506 binding protein 12-rapamycin associated protein 1 [Homosapiens]; (2043:) FK506 binding protein 5 [Homo sapiens]; (2044:)FK506-binding protein 10 precursor (Peptidyl-prolyl cis-transisomerase)(PPIase) (Rotamase) (65 kDa FK506-binding protein) (FKBP65)(Immunophilin FKBP65); (2045:) FK506-binding protein 1A (Peptidyl-prolylcis-trans isomerase) (PPIase) (Rotamase) (12 kDa FKBP) (FKBP-12)(Immunophilin FKBP12); (2046:) FK506-binding protein 1A [Homo sapiens];(2047:) FK506-binding protein 1B (Peptidyl-prolyl cis-trans isomerase1B) (PPIase 1B) (Rotamase 1B) (12.6 kDa FKBP) (FKBP-12.6) (ImmunophilinFKBP12.6) (h-FKBP-12); (2048:) FK506-binding protein 1B isoform a [Homosapiens]; (2049:) FK506-binding protein 1B isoform b [Homo sapiens];(2050:) FK506-binding protein 2 precursor (Peptidyl-prolylcis-transisomerase) (PPIase) (Rotamase) (13 kDa FKBP) (FKBP-13); (2051:)FK506-binding protein 3 (Peptidyl-prolyl cis-trans isomerase) (PPIase)(Rotamase) (25 kDa FKBP) (FKBP-25) (Rapamycin-selective 25 kDaimmunophilin); (2052:) FK506-binding protein 4 [Homo sapiens]; (2053:)FK506-binding protein 5 (Peptidyl-prolyl cis-trans isomerase) (PPIase)(Rotamase) (51 kDa FK506-binding protein) (FKBP-51) (54 kDa progesteronereceptor-associated immunophilin) (FKBP54) (P54) (FF1 antigen)(HSP90-binding immunophilin) (Androgen-regulated protein 6); (2054:)FK506-binding protein 6 [Homo sapiens]; (2055:) FK506-binding protein 9precursor (Peptidyl-prolyl cis-transisomerase) (PPIase) (Rotamase);(2056:) FL cytokine receptor precursor (Tyrosine-protein kinase receptorFLT3) (Stem cell tyrosine kinase 1) (STK-1) (CD135 antigen); (2057:)FLAD1 protein [Homo sapiens]; (2058:) FLAME-1 [Homo sapiens]; (2059:)FLAME-1-beta [Homo sapiens]; (2060:) FLAME-1-delta [Homo sapiens];(2061:) FLAME-1-gamma [Homo sapiens]; (2062:) flap structure-specificendonuclease 1 [Homo sapiens]; (2063:) flavin adenine dinucleotidesynthetase isoform 1 [Homo sapiens]; (2064:) flavin adenine dinucleotidesynthetase isoform 2 [Homo sapiens]; (2065:) flavin containingmonooxygenase 1 [Homo sapiens]; (2066:) flavin containing monooxygenase2 (non-functional) [Homo sapiens]; (2067:) flavin containingmonooxygenase 4 [Homo sapiens]; (2068:) flavin containing monooxygenase5 [Homo sapiens]; (2069:) Flavin reductase (FR) (NADPH-dependentdiaphorase) (NADPH-flavin reductase) (FLR) (Biliverdin reductase B)(BVR-B) (Biliverdin-IX beta-reductase) (Green heme-binding protein)(GHBP); (2070:) FLICE-like inhibitory protein long form [Homo sapiens];(2071:) FLJ00013 protein [Homo sapiens]; (2072:) FLJ00207 protein [Homosapiens]; (2073:) FLJ00405 protein [Homo sapiens]; (2074:) FLJ11011[Homo sapiens]; (2075:) FLJ12389 protein [Homo sapiens]; (2076:)FLJ13855 [Homo sapiens]; (2077:) FLJ20581 protein [Homo sapiens];(2078:) FLJ21963 protein [Homo sapiens]; (2079:) fMet-Leu-Phe receptor(fMLP receptor) (N-formyl peptide receptor) (FPR) (N-formyl peptidechemoattractant receptor); (2080:) FMLP-related receptor I (FMLP-R-1)(Lipoxin A4 receptor) (LXA4receptor) (Formyl peptide receptor-like 1)(RFP) (HM63); (2081:) FMLP-related receptor 11 (FMLP-R-II)(Formylpeptide receptor-like2); (2082:) fms-related tyrosine kinase 1(vascular endothelial growth factor/vascular permeability factorreceptor) [Homo sapiens]; (2083:) folate hydrolase 1 isoform 1 [Homosapiens]; (2084:) folate hydrolase 1 isoform 2 [Homo sapiens]; (2085:)Folate receptor alpha precursor (FR-alpha) (Folate receptor 1) (Folatereceptor, adult) (Adult folate-binding protein) (FBP) (Ovariantumor-associated antigen MOv18) (KB cells FBP); (2086:) Folate receptorbeta precursor (FR-beta) (Folate receptor 2) (Folate receptor,fetal/placental) (Placental folate-binding protein) (FBP); (2087:)Folate receptor gamma precursor (FR-gamma) (Folate receptor 3); (2088:)Follicle-stimulating hormone receptor precursor (FSH-R) (Follitropinreceptor); (2089:) folylpolyglutamate synthase isoform a precursor [Homosapiens]; (2090:) folylpolyglutamate synthase isoform b [Homo sapiens];(2091:) Folylpolyglutamate synthase, mitochondrial precursor(Folylpoly-gamma-glutamate synthetase) (FPGS) (Tetrahydrofolatesynthase)(Tetrahydrofolylpolyglutamate synthase); (2092:)“Formimidoyltransferase-cyclodeaminase(Formiminotransferase-cyclodeaminase) (FTCD) (LCHC1) [Includes:Glutamateformimidoyltransferase (Glutamate formiminotransferase) (Glutamateformyltransferase); Formimidoyltetrahydrofolatecyclodeaminase(Formiminotetrahydrofolate cyclodeaminase)].”; (2093:)formiminotransferase cyclodeaminase [Homo sapiens]; (2094:) fragilehistidine triad gene [Homo sapiens]; (2095:) frataxin isoform 1preproprotein [Homo sapiens]; (2096:) frataxin isoform 2 preproprotein[Homo sapiens]; (2097:) Free fatty acid receptor 1 (G-protein coupledreceptor 40); (2098:) Free fatty acid receptor 2 (G-protein coupledreceptor 43); (2099:) Free fatty acid receptor 3 (G-protein coupledreceptor 41); (2100:) Frizzled-1 precursor (Fz-1) (hFz1) (FzE1); (2101:)Frizzled-10 precursor (Fz-10) (hFz10) (FzE7); (2102:) Frizzled-2precursor (Fz-2) (hFz2) (FzE2); (2103:) Frizzled-3 precursor (Fz-3)(hFz3); (2104:) Frizzled-4 precursor (Fz-4) (hFz4) (FzE4); (2105:)Frizzled-5 precursor (Fz-5) (hFz5) (FzE5); (2106:) Frizzled-6 precursor(Fz-6) (hFz6); (2107:) Frizzled-7 precursor (Fz-7) (hFz7) (FzE3);(2108:) Frizzled-8 precursor (Fz-8) (hFz8); (2109:) Frizzled-9 precursor(Fz-9) (hFz9) (FzE6) (CD349 antigen); (2110:) fructosamine 3 kinase[Homo sapiens]; (2111:) fructosamine-3-kinase-related protein [Homosapiens]; (2112:) fructose-1,6-bisphosphatase [Homo sapiens]; (2113:)Fructose-1,6-bisphosphatase 1(D-fructose-1,6-bisphosphate1-phosphohydrolase 1) (FBPase 1); (2114:)fructose-1,6-bisphosphatase 1 [Homo sapiens]; (2115:)fructose-1,6-bisphosphatase 1 variant [Homo sapiens]; (2116:)fructose-1,6-bisphosphatase 2 [Homo sapiens]; (2117:)Fructose-1,6-bisphosphatase isozyme 2(D-fructose-1,6-bisphosphate1-phosphohydrolase 2) (FBPase 2); (2118:)fructose-1,6-bisphosphatase; (2119:) fructose-6-phosphate,2-kinase/fructose-2,6-bisphosphatase [Homo sapiens]; (2120:)Fructose-bisphosphate aldolase A (Muscle-type aldolase) (Lung cancerantigen NY-LU-1); (2121:) Fructose-bisphosphate aldolase B (Liver-typealdolase); (2122:) Fructose-bisphosphate aldolase C (Brain-typealdolase); (2123:) fructose-bisphosphate aldolase C [Homo sapiens];(2124:) fucokinase [Homo sapiens]; (2125:) fucose-1-phosphateguanyltransferase [Homo sapiens]; (2126:) Fucose-1-phosphateguanylyltransferase (GDP-L-fucosepyrophosphorylase) (GDP-L-fucosediphosphorylase); (2127:) fucosidase, alpha-L-1, tissue [Homo sapiens];(2128:) fucosidase, alpha-L-2, plasma [Homo sapiens]; (2129:)fucosyltransferase 1 [Homo sapiens]; (2130:) fucosyltransferase 2(secretor status included) [Homo sapiens]; (2131:) fucosyltransferase 3(galactoside 3(4)-L-fucosyltransferase, Lewis blood group included)[Homo sapiens]; (2132:) fucosyltransferase 5 [Homo sapiens]; (2133:)fucosyltransferase 8 isoform a [Homo sapiens]; (2134:)fucosyltransferase 8 isoform b [Homo sapiens]; (2135:)fucosyltransferase 8 isoform c [Homo sapiens]; (2136:) fukutin-relatedprotein [Homo sapiens]; (2137:) fumarate hydratase precursor [Homosapiens]; (2138:) Fumarylacetoacetase (Fumarylacetoacetate hydrolase)(Beta-diketonase) (FM); (2139:) fumarylacetoacetate hydrolase(fumarylacetoacetase) [Homo sapiens]; (2140:) Furin (paired basic aminoacid cleaving enzyme) [Homo sapiens]; (2141:) Furin precursor (Pairedbasic amino acid residue cleaving enzyme) (PACE) (Dibasic-processingenzyme); (2142:) furin preproprotein [Homo sapiens]; (2143:) Fused toesprotein homolog (Ft1); (2144:) FXYD domain containing ion transportregulator 3 isoform 1precursor [Homo sapiens]; (2145:) FXYD domaincontaining ion transport regulator 3 isoform 2precursor [Homo sapiens];(2146:) FXYD domain-containing ion transport regulator 2 isoform 1 [Homosapiens]; (2147:) FXYD domain-containing ion transport regulator 2isoform 2 [Homo sapiens]; (2148:) FXYD domain-containing ion transportregulator 5 [Homo sapiens]; (2149:) FXYD domain-containing ion transportregulator 6 [Homo sapiens]; (2150:) FXYD domain-containing ion transportregulator 7 [Homo sapiens]; (2151:) G protein-coupled bile acid receptor1 [Homo sapiens]; (2152:) G protein-coupled receptor kinase-interactor 2isoform 1 [Homo sapiens]; (2153:) G protein-coupled receptorkinase-interactor 2 isoform 2 [Homo sapiens]; (2154:) G protein-coupledreceptor kinase-interactor 2 isoform 3 [Homo sapiens]; (2155:) Gprotein-coupled receptor kinase-interactor 2 isoform 4 [Homo sapiens];(2156:) G/T mismatch-specific thymine DNA glycosylase; (2157:) G6bprotein precursor; (2158:) GA binding protein transcription factor,alpha subunit (60 kD) [Homo sapiens]; (2159:) GABA(A)receptor-associated protein [Homo sapiens]; (2160:) Galactocerebrosidaseprecursor (GALCERase) (Galactosylceramidase) (Galactosylceramidebeta-galactosidase) (Galactocerebroside beta-galactosidase); (2161:)Galactokinase (Galactose kinase); (2162:) galactokinase 1 [Homosapiens]; (2163:) galactose mutarotase (aldose 1-epimerase) [Homosapiens]; (2164:) galactose-1-phosphate uridyl transferase [Homosapiens]; (2165:) galactose-1-phosphate uridyl transferase; (2166:)Galactose-1-phosphate uridylyltransferase (Gal-1-Puridylyltransferase)(UDP-glucose—hexose-1-phosphateuridylyltransferase); (2167:)galactose-1-phosphate uridylyltransferase [Homo sapiens]; (2168:)galactose-3-O-sulfotransferase [Homo sapiens]; (2169:)Galactose-3-O-sulfotransferase 2 (Gal3ST-2)(Galbeta1-3GalNAc3′-sulfotransferase 2)(Beta-galactose-3-O-sulfotransferase 2) (Glycoprotein beta-Gal3′-sulfotransferase 2); (2170:) galactose-3-O-sulfotransferase 2 [Homosapiens]; (2171:) galactosidase, alpha [Homo sapiens]; (2172:)galactosidase, beta 1 [Homo sapiens]; (2173:) Galactoside2-alpha-L-fucosyltransferase 1(GDP-L-fucose:beta-D-galactoside2-alpha-L-fucosyltransferase 1) (Alpha(1,2)FT 1) (Fucosyltransferase 1)(Blood group H alpha2-fucosyltransferase); (2174:) Galactoside2-alpha-L-fucosyltransferase 2(GDP-L-fucose:beta-D-galactoside2-alpha-L-fucosyltransferase 2) (Alpha(1,2)FT 2) (Fucosyltransferase 2)(Secretor blood group alpha-2-fucosyltransferase) (Secretor factor) (Se)(SE2); (2175:) Galactoside 3(4)-L-fucosyltransferase (Blood group Lewisalpha-4-fucosyltransferase) (Lewis FT) (Fucosyltransferase 3)(FUCT-III); (2176:) galactosyl transferase-associated protein [Homosapiens]; (2177:) galactosylceramidase (EC 3.2.1.46) precursor-human;(2178:) galactosylceramidase isoform a precursor [Homo sapiens]; (2179:)galactosylceramidase isoform b precursor [Homo sapiens]; (2180:)Galactosylgalactosylxylosyl protein 3-beta-glucuronosyltransferase 1(Beta-1,3-glucuronyltransferase 1) (Glucuronosyltransferase-P) (GlcAT-P)(UDP-GlcUA:glycoprotein beta-1,3-glucuronyltransferase) (GlcUAT-P);(2181:) Galactosylgalactosylxylosyl protein3-beta-glucuronosyltransferase 2(Beta-1,3-glucuronyltransferase 2)(Glucuronosyltransferase-S) (GlcAT-S) (UDP-glucuronosyltransferase-S)(GlcAT-D); (2182:) galactosylgalactosylxylosyl protein3-beta-glucuronosyltransferase 2 [Homo sapiens]; (2183:)Galactosylgalactosylxylosyl protein 3-beta-glucuronosyltransferase3(Beta-1,3-glucuronyltransferase 3) (Glucuronosyltransferase-1)(GlcAT-1) (UDP-GlcUA:Gal beta-1,3-Gal-R glucuronyltransferase)(GlcUAT-1); (2184:) Galanin receptor type 1 (GAL1-R) (GALR1); (2185:)Galanin receptor type 2 (GAL2-R) (GALR2); (2186:) Galanin receptor type3 (GAL3-R) (GALR3); (2187:) galctocerebrosidase; (2188:) galectin 3[Homo sapiens]; (2189:) GalNAc 4-sulfotransferase [Homo sapiens];(2190:) gamma isoform of regulatory subunit B55, protein phosphatase 2isoform a [Homo sapiens]; (2191:) gamma isoform of regulatory subunitB55, protein phosphatase 2 isoform b [Homo sapiens]; (2192:) gammaisoform of regulatory subunit B56, protein phosphatase 2A isoform a[Homo sapiens]; (2193:) gamma isoform of regulatory subunit B56, proteinphosphatase 2A isoform b [Homo sapiens]; (2194:) gamma isoform ofregulatory subunit B56, protein phosphatase 2A isoform c [Homo sapiens];(2195:) gamma isoform of regulatory subunit B56, protein phosphatase 2Aisoform d [Homo sapiens]; (2196:) Gamma-aminobutyric acid type Breceptor, subunit 1 precursor (GABA-B receptor 1) (GABA-B-R1) (Gb1);(2197:) Gamma-aminobutyric acid type B receptor, subunit 2 precursor(GABA-B receptor 2) (GABA-B-R2) (Gb2) (GABABR2) (G-protein coupledreceptor 51) (HG20); (2198:) gamma-butyrobetaine dioxygenase [Homosapiens]; (2199:) gamma-catenin [Homo sapiens]; (2200:) gamma-glutamylcarboxylase [Homo sapiens]; (2201:) gamma-glutamyl hydrolase (EC3.4.19.9)—human; (2202:) Gamma-glutamyl hydrolase precursor (Gamma-Glu-Xcarboxypeptidase) (Conjugase) (GH); (2203:) gamma-glutamyl hydrolaseprecursor [Homo sapiens]; (2204:) gamma-glutamyltransferase 1 precursor[Homo sapiens]; (2205:) “Gamma-glutamyltransferase 5 precursor(Gamma-glutamyltranspeptidase 5) (Gamma-glutamyltransferase-likeactivity 1) (GGT-rel) [Contains:Gamma-glutamyltransferase 5 heavy chain;Gamma-glutamyltransferase 5 light chain].”; (2206:)gamma-glutamyltransferase-like activity 1 [Homo sapiens]; (2207:)gamma-glutamyltransferase-like activity 4 [Homo sapiens]; (2208:)“Gamma-glutamyltranspeptidase 1 precursor (Gamma-glutamyltransferase 1)(GGT 1) (CD224 antigen) [Contains:) Gamma-glutamyltranspeptidase 1 heavychain; Gamma-glutamyltranspeptidase 1 light chain].”; (2209:)gamma-glutmyl transpeptidase-related protein; (2210:) Gamma-secretasesubunit APH-1A (APH-1a) (Aph-1 alpha) (Presenilin-stabilization factor);(2211:) Gamma-secretase subunit PEN-2 (Presenilin enhancer protein 2);(2212:) ganglioside-specific alpha-2,8-polysialyltransferase; (2213:)gastric inhibitory polypeptide preproprotein [Homo sapiens]; (2214:)Gastric inhibitory polypeptide receptor precursor (GIP-R)(Glucose-dependent insulinotropic polypeptide receptor); (2215:) gastriclipase precursor [Homo sapiens]; (2216:) Gastric triacylglycerol lipaseprecursor (Gastric lipase) (GL); (2217:) Gastrin/cholecystokinin type Breceptor (CCK-B receptor) (CCK-BR) (Cholecystokinin-2 receptor)(CCK2-R); (2218:) gastrin-releasing peptide isoform 1 preproprotein[Homo sapiens]; (2219:) gastrin-releasing peptide isoform 2preproprotein [Homo sapiens]; (2220:) gastrin-releasing peptide isoform3 preproprotein [Homo sapiens]; (2221:) Gastrin-releasing peptidereceptor (GRP-R) (GRP-preferring bombesin receptor); (2222:) GCNT2 [Homosapiens]; (2223:) GCNT3 protein [Homo sapiens]; (2224:) GDNF familyreceptor alpha-1 precursor (GFR-alpha-1) (GDNF receptor alpha)(GDNFR-alpha) (TGF-beta-related neurotrophic factor receptor1) (RETligand 1); (2225:) GDNF family receptor alpha-2 precursor (GFR-alpha-2)(Neurturin receptor alpha) (NTNR-alpha) (NRTNR-alpha) (TGF-beta-relatedneurotrophic factor receptor 2) (GDNF receptor beta) (GDNFR-beta) (RETligand 2); (2226:) GDNF family receptor alpha-3 precursor (GFR-alpha-3);(2227:) GDNF family receptor alpha-4 precursor (GFR-alpha-4) (Persephinreceptor); (2228:) GDNF family receptor alpha-like precursor; (2229:)GDP-D-mannose-4,6-dehydratase [Homo sapiens]; (2230:) GDP-L-fucosepyrophosphorylase [Homo sapiens]; (2231:) GDP-mannose 4,6-dehydratase[Homo sapiens]; (2232:) GDP-mannose pyrophosphorylase A [Homo sapiens];(2233:) GDP-mannose pyrophosphorylase β isoform 1 [Homo sapiens];(2234:) GDP-mannose pyrophosphorylase β isoform 2 [Homo sapiens];(2235:) gelatinase, type IV collagenase {N-terminal} [human,neutrophils, Peptide Partial, 19 aa]; (2236:) Gephyrin [Homo sapiens];(2237:) gephyrin isoform 1 [Homo sapiens]; (2238:) gephyrin isoform 2[Homo sapiens]; (2239:) geranylgeranyl diphosphate synthase 1 isoform A[Homo sapiens]; (2240:) geranylgeranyl diphosphate synthase 1 isoform B[Homo sapiens]; (2241:) geranylgeranyl transferase 11 [Homo sapiens];(2242:)

Geranylgeranyl transferase type-2 alpha subunit (Geranylgeranyltransferase type 11 alpha subunit) (Rab geranylgeranyl transferase alphasubunit) (Rab geranyl-geranyl transferase alpha subunit) (RabGGtransferase alpha) (Rab GGTase alpha); (2243:) Geranylgeranyltransferase type-2 subunit beta (Geranylgeranyl transferase type IIsubunit beta) (Rab geranylgeranyl transferase subunit beta) (Rabgeranyl-geranyl transferase subunit beta) (Rab GG transferase beta) (RabGGTase beta); (2244:) ghrelin precursor [Homo sapiens]; (2245:)GlcNac-1-P transferase [Homo sapiens]; (2246:) GlcNAc-phosphotransferaseprecursor [Homo sapiens]; (2247:) Globosidealpha-1,3-N-acetylgalactosaminyltransferase 1 (Forssmanglycolipidsynthetase-like protein); (2248:) glomulin [Homo sapiens]; (2249:)Glucagon receptor precursor (GL-R); (2250:) Glucagon-like peptide 1receptor precursor (GLP-1 receptor) (GLP-1-R) (GLP-1R); (2251:)Glucagon-like peptide 2 receptor precursor (GLP-2 receptor) (GLP-2-R)(GLP-2R); (2252:) glucan (1,4-alpha-), branching enzyme 1 (glycogenbranching enzyme)[Homo sapiens]; (2253:) Glucan, branching enzyme 1variant [Homo sapiens]; (2254:) glucocerebrosidase precursor [Homosapiens]; (2255:) Glucocorticoid receptor (GR); (2256:) Glucokinase(Hexokinase-4) (Hexokinase type IV) (HK IV) (HK4) (Hexokinase-D);(2257:) glucokinase isoform 1 [Homo sapiens]; (2258:) glucokinaseisoform 2 [Homo sapiens]; (2259:) glucokinase isoform 3 [Homo sapiens];(2260:) Glucokinase regulatory protein (Glucokinase regulator); (2261:)glucokinase regulatory protein [Homo sapiens]; (2262:) glucosamine(N-acetyl)-6-sulfatase precursor [Homo sapiens]; (2263:)glucosamine-fructose-6-phosphate aminotransferase [Homo sapiens];(2264:) Glucosaminyl (N-acetyl) transferase 1, core2(beta-1,6-N-acetylglucosaminyltransferase) [Homo sapiens]; (2265:)Glucosaminyl (N-acetyl) transferase 2,1-branching enzyme (I blood group)[Homo sapiens]; (2266:) glucosaminyl (N-acetyl) transferase2,1-branching enzyme isoform A[Homo sapiens]; (2267:) glucosaminyl(N-acetyl) transferase 2,1-branching enzyme isoform B [Homo sapiens];(2268:) glucosaminyl (N-acetyl) transferase 2,1-branching enzyme isoformC[Homo sapiens]; (2269:) Glucosaminyl (N-acetyl) transferase 2,I-branching enzyme, isoform B [Homo sapiens]; (2270:) glucosaminyl(N-acetyl) transferase 3, mucin type [Homo sapiens]; (2271:) glucosephosphate isomerase [Homo sapiens]; (2272:) glucose transporter 4 [Homosapiens]; (2273:) Glucose-6-phosphatase (G6 Pase) (G-6-Pase); (2274:)glucose-6-phosphatase, catalytic subunit [Homo sapiens]; (2275:)Glucose-6-phosphate 1-dehydrogenase (G6PD); (2276:) glucose-6-phosphatedehydrogenase isoform a [Homo sapiens]; (2277:) glucose-6-phosphatedehydrogenase isoform b [Homo sapiens]; (2278:) “glucosidase, alpha;neutral C [Homo sapiens].”; (2279:) glucuronidase, beta [Homo sapiens];(2280:) glucuronyltransferase [Homo sapiens]; (2281:)glucuronyltransferase I [Homo sapiens]; (2282:) Glutamate [NMDA]receptor subunit 3A precursor (N-methyl-D-aspartate receptor subtypeNR3A) (NMDAR-L); (2283:) Glutamate [NMDA] receptor subunit 3B precursor(N-methyl-D-aspartate receptor subtype NR3B) (NR3B) (NMDAR3B); (2284:)Glutamate [NMDA] receptor subunit epsilon 1 precursor (N-methylD-aspartate receptor subtype 2A) (NR2A) (NMDAR2A) (hNR2A); (2285:)Glutamate [NMDA] receptor subunit epsilon 2 precursor (N-methylD-aspartate receptor subtype 2B) (NR2B) (NM DAR2B) (N-methyl-D-aspartatereceptor subunit 3) (NR3) (hNR3); (2286:) Glutamate [NMDA] receptorsubunit epsilon 3 precursor (N-methyl D-aspartate receptor subtype 2C)(NR2C) (NMDAR2C); (2287:) Glutamate [NMDA] receptor subunit epsilon 4precursor (N-methyl D-aspartate receptor subtype 2D) (NR2D) (NMDAR2D)(EB11); (2288:) Glutamate [NMDA] receptor subunit zeta 1 precursor(N-methyl-D-aspartate receptor subunit NR1); (2289:) Glutamatecarboxypeptidase 2 (Glutamate carboxypeptidase II) (Membrane glutamatecarboxypeptidase) (mGCP) (N-acetylated-alpha-linked acidicdipeptidase 1) (NAALADase I) (Pteroylpoly-gamma-glutamatecarboxypeptidase) (Folylpoly-gamma-glutamate carboxypeptidase) (FGCP)(Folatehydrolase 1) (Prostate-specific membrane antigen) (PSMA) (PSM);(2290:) Glutamate decarboxylase 1 (Glutamate decarboxylase 67 kDaisoform) (GAD-67) (67 kDa glutamic acid decarboxylase); (2291:)glutamate decarboxylase 1 isoform GAD25 [Homo sapiens]; (2292:)glutamate decarboxylase 1 isoform GAD67 [Homo sapiens]; (2293:)glutamate decarboxylase 2 [Homo sapiens]; (2294:) glutamatedehydrogenase 1 [Homo sapiens]; (2295:) Glutamate dehydrogenase 1,mitochondrial precursor (GDH); (2296:) glutamate dehydrogenase 2 [Homosapiens]; (2297:) Glutamate receptor 1 precursor (GluR-1) (GluR-A)(GluR-K1) (Glutamate receptor ionotropic, AMPA 1) (AMPA-selectiveglutamate receptor 1); (2298:) Glutamate receptor 2 precursor (GluR-2)(GluR-B) (GluR-K2) (Glutamate receptor ionotropic, AMPA 2)(AMPA-selective glutamate receptor 2); (2299:) Glutamate receptor 3precursor (GluR-3) (GluR-C) (GluR-K3) (Glutamate receptor ionotropic,AMPA 3) (AMPA-selective glutamate receptor 3); (2300:) Glutamatereceptor 4 precursor (GluR-4) (GluR4) (GluR-D) (Glutamate receptorionotropic, AMPA 4) (AMPA-selective glutamate receptor 4); (2301:)Glutamate receptor delta-1 subunit precursor (GluR delta-1); (2302:)Glutamate receptor delta-2 subunit precursor (GluR delta-2); (2303:)Glutamate receptor, ionotropic kainate 1 precursor (Glutamate receptor5) (GluR-5) (GluR5) (Excitatory amino acid receptor 3) (EM3); (2304:)Glutamate receptor, ionotropic kainate 2 precursor (Glutamate receptor6) (GluR-6) (GluR6) (Excitatory amino acid receptor 4) (EAA4); (2305:)Glutamate receptor, ionotropic kainate 3 precursor (Glutamate receptor7) (GluR-7) (GluR7) (Excitatory amino acid receptor 5) (EAA5); (2306:)Glutamate receptor, ionotropic kainate 4 precursor (Glutamate receptorKA-1) (KA1) (Excitatory amino acid receptor 1) (EAA1); (2307:) Glutamatereceptor, ionotropic kainate 5 precursor (Glutamate receptor KA-2) (KA2)(Excitatory amino acid receptor 2) (EAA2); (2308:)glutamate-5-semialdehyde dehydrogenase (EC 1.2.1.41)—human (fragments);(2309:) Glutamate—cysteine ligase catalytic subunit (Gamma-glutamylcysteine synthetase) (Gamma-ECS) (GCS heavy chain); (2310:)glutamate-cysteine ligase regulatory protein [Homo sapiens]; (2311:)glutamate-cysteine ligase, catalytic subunit [Homo sapiens]; (2312:)glutamic gamma-semialdehyde dehydrogenase; (2313:) glutaminase 2 [Homosapiens]; (2314:) glutaminase C [Homo sapiens]; (2315:) glutaminesynthetase [Homo sapiens]; (2316:) glutaminyl-peptide cyclotransferaseprecursor [Homo sapiens]; (2317:) Glutaminyl-tRNA synthetase(Glutamine—tRNA ligase) (GlnRS); (2318:) glutaminyl-tRNA synthetase[Homo sapiens]; (2319:) Glutaredoxin-2, mitochondrial precursor; (2320:)glutaryl-CoA dehydrogenase [Homo sapiens]; (2321:) Glutaryl-CoAdehydrogenase, mitochondrial precursor (GCD); (2322:) glutaryl-CoenzymeA dehydrogenase isoform a precursor [Homo sapiens]; (2323:)glutaryl-Coenzyme A dehydrogenase isoform b precursor [Homo sapiens];(2324:) glutathione peroxidase [Homo sapiens]; (2325:) glutathioneperoxidase 1 isoform 1 [Homo sapiens]; (2326:) glutathione peroxidase 1isoform 2 [Homo sapiens]; (2327:) glutathione peroxidase 4 isoform Aprecursor [Homo sapiens]; (2328:) glutathione peroxidase 4 isoform Bprecursor [Homo sapiens]; (2329:) glutathione peroxidase 4 isoform Cprecursor [Homo sapiens]; (2330:) Glutathione Reductase (E.C.1.6.4.2)(Oxidized) Complex With Glutathione Disulfide And Nadp+; (2331:)Glutathione Reductase (E.C.1.6.4.2) Carboxymethylated At Cys 58 ComplexWith Phosphate; (2332:) Glutathione Reductase (E.C.1.6.4.2) Complex WithCovalently Bound Glutathione And Phosphate; (2333:) GlutathioneReductase (E.C.1.6.4.2) Modified ByBcnu(1,3-Bis(2-Chloroethyl)-1-Nitrosourea) At Cys 58 Complexed WithPhosphate; (2334:) Glutathione Reductase (E.C.1.6.4.2) Modified ByHecnu(1-(2-Chloroethyl)-3-(2-Hydroxyethyl)-1-Nitrosourea) At Cys58Complexed With Phosphate; (2335:) glutathione reductase [Homosapiens]; (2336:) Glutathione reductase, mitochondrial precursor (GR)(GRase); (2337:) glutathione S-transferase A1 [Homo sapiens]; (2338:)glutathione S-transferase A3 [Homo sapiens]; (2339:) GlutathioneS-transferase A4 (Glutathione S-transferase A4-4) (GST class-alphamember 4); (2340:) glutathione S-transferase A4 [Homo sapiens]; (2341:)glutathione S-transferase M1 isoform 1 [Homo sapiens]; (2342:)glutathione S-transferase M1 isoform 2 [Homo sapiens]; (2343:)glutathione S-transferase M3 [Homo sapiens]; (2344:) GlutathioneS-transferase Mu 1 (GSTM1-1) (GST class-mu 1) (GSTM1a-1a) (GSTM1b-1b)(HB subunit 4) (GTH4); (2345:) glutathione S-transferase theta 1 [Homosapiens]; (2346:) Glutathione S-transferase theta-1 (GST class-theta-1)(Glutathione transferase T1-1); (2347:) glutathione transferase [Homosapiens]; (2348:) glutathione transferase A4-4 [Homo sapiens]; (2349:)glutathione transferase kappa 1 [Homo sapiens]; (2350:) glutathionetransferase T1-1 [Homo sapiens]; (2351:) glutathione transferase zeta 1isoform 1 [Homo sapiens]; (2352:) glutathione transferase zeta 1 isoform2 [Homo sapiens]; (2353:) glutathione transferase zeta 1 isoform 3 [Homosapiens]; (2354:) glutathione transferase; (2355:)glyceraldehyde-3-phosphate dehydrogenase [Homo sapiens]; (2356:)Glycerol kinase (ATP:glycerol 3-phosphotransferase) (Glycerokinase)(GK); (2357:) Glycerol kinase, testis specific 1(ATP:glycerol3-phosphotransferase) (Glycerokinase) (GK); (2358:)Glycerol kinase, testis specific 2 (ATP:glycerol3-phosphotransferase)(Glycerokinase) (GK); (2359:) glycerol-3-phosphate dehydrogenase 2(mitochondrial) [Homo sapiens]; (2360:) Glycerol-3-phosphatedehydrogenase, mitochondrial precursor (GPD-M) (GPDH-M) (mtGPD); (2361:)glycine amidino transferase (L-arginine:glycine amidinotransferase)[Homo sapiens]; (2362:) Glycine amidino transferase,mitochondrial precursor (L-arginine:glycine amidino transferase)(Transamidinase) (AT); (2363:) Glycine C-acetyltransferase(2-amino-3-ketobutyrate coenzyme Aligase) [Homo sapiens]; (2364:)glycine C-acetyltransferase precursor [Homo sapiens]; (2365:) Glycinecleavage system H protein, mitochondrial precursor; (2366:) glycinecleavage system protein H (aminomethyl carrier) [Homo sapiens]; (2367:)glycine dehydrogenase (decarboxylating) [Homo sapiens]; (2368:) glycineN-methyltransferase [Homo sapiens]; (2369:) Glycine receptor subunitalpha-1 precursor (Glycine receptor 48 kDa subunit) (Glycine receptorstrychnine-binding subunit); (2370:) Glycine receptor subunit alpha-2precursor; (2371:) Glycine receptor subunit alpha-3 precursor; (2372:)Glycine receptor subunit beta precursor (Glycine receptor 58 kDasubunit); (2373:) glycine-N-acyltransferase isoform a [Homo sapiens];(2374:) glycine-N-acyltransferase isoform b [Homo sapiens]; (2375:)glycoasparaginase; (2376:) Glycogen [starch] synthase, liver; (2377:)Glycogen [starch] synthase, muscle; (2378:) “Glycogen debranching enzyme(Glycogen debrancher) [Includes: 4-alpha-glucanotransferase(Oligo-1,4-1,4-glucantransferase); Amylo-alpha-1,6-glucosidase(Amylo-1,6-glucosidase) (Dextrin6-alpha-D-glucosidase)].”; (2379:)glycogen debranching enzyme [Homo sapiens]; (2380:) glycogen debranchingenzyme isoform 1 [Homo sapiens]; (2381:) glycogen debranching enzymeisoform 2 [Homo sapiens]; (2382:) glycogen debranching enzyme isoform 3[Homo sapiens]; (2383:) glycogen debranching enzyme isoform 4 [Homosapiens]; (2384:) glycogen debranching enzyme isoform 6 [Homo sapiens];(2385:) glycogen phosphorylase [Homo sapiens]; (2386:) Glycogenphosphorylase, brain form; (2387:) Glycogen phosphorylase, liver form;(2388:) Glycogen phosphorylase, muscle form (Myophosphorylase); (2389:)glycogen synthase kinase 3 beta [Homo sapiens]; (2390:) Glycogensynthase kinase-3 beta (GSK-3 beta); (2391:) glycogen-debranching enzyme[Homo sapiens]; (2392:) glycophorin A precursor [Homo sapiens]; (2393:)glycoprotein V (platelet) [Homo sapiens]; (2394:)glycoprotein-fucosylgalactosidealpha-N-acetylgalactosaminyltransferase(EC 2.4.1.40) A1 allele [validated]—human; (2395:)glycosylphosphatidylinositol specific phospholipase D1 isoform 1precursor [Homo sapiens]; (2396:) glycosylphosphatidylinositol specificphospholipase D1 isoform 2precursor [Homo sapiens]; (2397:) Glycylpeptide N-tetradecanoyltransferase 1 (Peptide N-myristoyltransferase 1)(Myristoyl-CoA:protein N-myristoyltransferase 1) (NMT 1) (Type IN-myristoyltransferase); (2398:) glycyl-tRNA synthetase [Homo sapiens];(2399:) glyoxalase I [Homo sapiens]; (2400:) glyoxylatereductase/hydroxypyruvate reductase [Homo sapiens]; (2401:) Glyoxylatereductase/hydroxypyruvate reductase; (2402:) GM2 ganglioside activatorprecursor [Homo sapiens]; (2403:) Golgi autoantigen, golgin subfamily a,2 [Homo sapiens]; (2404:) golgi autoantigen, golgin subfamily b,macrogolgin (with transmembrane signal), 1 [Homo sapiens]; (2405:) Golgireassembly stacking protein 1 [Homo sapiens]; (2406:) Golgi-specificbrefeldin A-resistance guanine nucleotide exchange factor 1(BFA-resistant GEF 1); (2407:) Golli-mbp isoform 1 [Homo sapiens];(2408:) Golli-mbp isoform 2 [Homo sapiens]; (2409:)Gonadotropin-releasing hormone 11 receptor (Type II GnRH receptor)(GnRH-II-R); (2410:) Gonadotropin-releasing hormone receptor (GnRHreceptor) (GnRH-R); (2411:) gp180-carboxypeptidase D-like enzyme [Homosapiens]; (2412:) GPI mannosyltransferase 1 (GPI mannosyltransferase 1)(GPI-MT-I) (Phosphatidylinositol-glycan biosynthesis class M protein)(PIG-M); (2413:) GPI mannosyltransferase 2 (GPI mannosyltransferase II)(GPI-MT-II) (Phosphatidylinositol-glycan biosynthesis class V protein)(PIG-V); (2414:) GPI transamidase component PIG-T precursor(Phosphatidylinositol-glycan biosynthesis class T protein); (2415:)GPI-anchor transamidase precursor (GPI transamidase)(Phosphatidylinositol-glycan biosynthesis class K protein) (PIG-K)(hGPI8); (2416:) G-protein coupled bile acid receptor 1 (Membrane-typereceptor forbile acids) (M-BAR) (hGPCR19) (BG37) (hBG37); (2417:)G-protein coupled receptor 120 (G-protein coupled receptor PGR4)(G-protein coupled receptor GTO01) (G-protein coupled receptor 129);(2418:) G-protein coupled receptor 143 (Ocular albinism type 1 protein);(2419:) G-protein coupled receptor 15 (BOB); (2420:) G-protein coupledreceptor 56 precursor (TM7XN1 protein); (2421:) G-protein coupledreceptor 64 precursor (Epididymis-specific protein 6) (He6 receptor);(2422:) G-protein coupled receptor 98 precursor (Monogenic audiogenicseizure susceptibility protein 1 homolog) (Very large G-protein coupledreceptor 1) (Usher syndrome type-2C protein); (2423:) G-protein coupledreceptor family C group 5 member B precursor (Retinoic acid-induced gene2 protein) (RAIG-2) (A-69G12.1); (2424:) G-protein coupled receptorfamily C group 5 member C precursor (Retinoic acid-induced gene 3protein) (RAIG-3); (2425:) G-protein coupled receptor family C group 5member D; (2426:) G-protein coupled receptor family C group 6 member Aprecursor (hGPRC6A) (G-protein coupled receptor 33) (hGPCR33); (2427:)Grainy head-like protein 1 homolog (Transcription factor CP2-like 2)(Transcription factor LBP-32) (NH32) (Mammalian grainy head); (2428:)Granulocyte colony-stimulating factor receptor precursor (G-CSF-R)(CD114 antigen); (2429:) Granulocyte-macrophage colony-stimulatingfactor receptor alpha chain precursor (GM-CSF-R-alpha) (GMR) (CD116antigen) (CDw116); (2430:) Granzyme A precursor (Cytotoxic T-lymphocyteproteinase 1) (Hanukkah factor) (H factor) (HF) (Granzyme-1) (CTLtryptase); (2431:) Granzyme B precursor (T-cell serine protease 1-3E)(Cytotoxic T-lymphocyte proteinase 2) (Lymphocyte protease) (SECT)(Granzyme-2) (Cathepsin G-like 1) (CTSGL1) (CTLA-1) (Human lymphocyteprotein) (HLP) (C11); (2432:) granzyme B precursor [Homo sapiens];(2433:) Granzyme H precursor (Cytotoxic T-lymphocyte proteinase)(Cathepsin G-like 2) (CTSGL2) (CCP-X) (Cytotoxic serine protease C)(CSP-C); (2434:) granzyme M precursor [Homo sapiens]; (2435:)Green-sensitive opsin (Green cone photoreceptor pigment); (2436:) Group3 secretory phospholipase A2 precursor (Group III secretoryphospholipase A2) (Phosphatidylcholine 2-acylhydrolase GIII)(GIIIsPLA2); (2437:) group III secreted phospholipase A2 [Homo sapiens];(2438:) growth factor receptor-bound protein 2 isoform 1 [Homo sapiens];(2439:) growth factor receptor-bound protein 2 isoform 2 [Homo sapiens];(2440:) growth hormone 1 isoform 1 [Homo sapiens]; (2441:) growthhormone 1 isoform 2 [Homo sapiens]; (2442:) growth hormone 1 isoform 3[Homo sapiens]; (2443:) growth hormone 1 isoform 4 [Homo sapiens];(2444:) growth hormone 1 isoform 5 [Homo sapiens]; (2445:) Growthhormone receptor precursor (GH receptor) (Somatotropin receptor)[Contains:) Growth hormone-binding protein (GH-binding protein) (GHBP)(Serum-binding protein)]; (2446:) Growth hormone secretagogue receptortype 1 (GHS-R) (GH-releasing peptide receptor) (GHRP) (Ghrelinreceptor); (2447:) Growth hormone-releasing hormone receptor precursor(GHRH receptor) (GRF receptor) (GRFR); (2448:) growth-inhibiting protein17 [Homo sapiens]; (2449:) G-T3 synthase; (2450:) GTP cyclohydrase I[Homo sapiens]; (2451:) GTP cyclohydrolase 1 isoform 1 [Homo sapiens];(2452:) GTP cyclohydrolase 1 isoform 2 [Homo sapiens]; (2453:) GTPcyclohydrolase 1 isoform 3 [Homo sapiens]; (2454:) GTP cyclohydrolase I(GTP-CH-1); (2455:) GTP cyclohydrolase I [Homo sapiens]; (2456:) GTPaseactivating Rap/RanGAP domain-like 1 isoform 1 [Homo sapiens]; (2457:)GTPase activating Rap/RanGAP domain-like 1 isoform 2 [Homo sapiens];(2458:) GTPase ERas precursor (E-Ras) (Embryonic stem cell-expressedRas); (2459:) GTPase HRas precursor (Transforming protein p21) (p21 ras)(H-Ras-1) (c-H-ras); (2460:) GTPase KRas (K-Ras 2) (Ki-Ras) (c-K-ras)(c-Ki-ras); (2461:) GTPase NRas precursor (Transforming protein N-Ras);(2462:) GTP-binding protein Rit1 (Ras-like protein expressed in manytissues) (Ras-like without CAAX protein 1); (2463:) guanine deaminase[Homo sapiens]; (2464:) guanine nucleotide exchange factor p532 [Homosapiens]; (2465:) guanosine monophosphate reductase [Homo sapiens];(2466:) guanylate cyclase 1, soluble, alpha 2 [Homo sapiens]; (2467:)guanylate cyclase activator 1A (retina) [Homo sapiens]; (2468:)“Guanylate cyclase activator 2B precursor [Contains:) GuanylatecyclaseC-activating peptide 2 (Guanylate cyclase C-activating peptide II)(GCAP-II); Uroguanylin (UGN)].”; (2469:) Guanylate cyclase solublesubunit alpha-2 (GCS-alpha-2); (2470:) Guanylate cyclase soluble subunitalpha-3 (GCS-alpha-3) (Soluble guanylate cyclase large subunit)(GCS-alpha-1); (2471:) Guanylate cyclase soluble subunit beta-1(GCS-beta-1) (Soluble guanylate cyclase small subunit) (GCS-beta-3);(2472:) Guanylate cyclase soluble subunit beta-2 (GCS-beta-2); (2473:)guanylate cyclase:SUBUNIT=alpha2; (2474:) “Guanylin precursor (Guanylatecyclase activator 2A) (Guanylatecyclase-activating protein 1) (Gap-1)[Contains:) HMW-guanylin; Guanylin].”; (2475:) H(+)-transportingtwo-sector ATPase [Homo sapiens]; (2476:) H⁺-exporting ATPase (EC3.6.3.6) chain D, vacuolar—human; (2477:) H2A histone family, member O[Homo sapiens]; (2478:) HACL1 protein [Homo sapiens]; (2479:) head andneck tumor and metastasis related protein [Homo sapiens]; (2480:) heatshock 27 kDa protein 1 [Homo sapiens]; (2481:) heat shock 27 kDa protein2 [Homo sapiens]; (2482:) heat shock 70 kDa protein 5 [Homo sapiens];(2483:) heat shock-like protein 1 [Homo sapiens]; (2484:) HEAT-like (PBSlyase) repeat containing 1 [Homo sapiens]; (2485:) Heat-stableenterotoxin receptor precursor (GC-C) (Intestinal guanylate cyclase)(STA receptor) (hSTAR); (2486:) hect domain and RLD 5 [Homo sapiens];(2487:) hedgehog acyltransferase [Homo sapiens]; (2488:) heme oxygenase(decyclizing) 1 [Homo sapiens]; (2489:) heme oxygenase (decyclizing) 2[Homo sapiens]; (2490:) heparan sulfate (glucosamine)3-O-sulfotransferase 5 [Homo sapiens]; (2491:) heparan sulfate(glucosamine) 3-O-sulfotransferase 6 [Homo sapiens]; (2492:) heparansulfate 2-O-sulfotransferase 1 [Homo sapiens]; (2493:) heparan sulfate3-O-sulfotransferase-1 precursor [Homo sapiens]; (2494:) heparan sulfate6-O-sulfotransferase [Homo sapiens]; (2495:) heparan sulfate6-O-sulfotransferase 3 [Homo sapiens]; (2496:) heparan sulfateD-glucosaminyl 3-O-sulfotransferase 2 [Homo sapiens]; (2497:) heparansulfate D-glucosaminyl 3-O-sulfotransferase 1 precursor[Homo sapiens];(2498:) heparan sulfate D-glucosaminyl 3-O-sulfotransferase 3A1 [Homosapiens]; (2499:) heparan sulfate D-glucosaminyl 3-O-sulfotransferase3B1 [Homo sapiens]; (2500:) heparan sulfate D-glucosaminyl3-O-sulfotransferase 4 [Homo sapiens]; (2501:) Heparan sulfateglucosamine 3-O-sulfotransferase 1 precursor (Heparan sulfateD-glucosaminyl 3-O-sulfotransferase 1) (Heparansulfate3-O-sulfotransferase 1) (h3-OST-1); (2502:) Heparan sulfate glucosamine3-O-sulfotransferase 3A1 (Heparansulfate D-glucosaminyl3-O-sulfotransferase 3A1) (Heparan sulfate3-O-sulfotransferase 3A1)(h3-OST-3A); (2503:) Heparan sulfate glucosamine 3-O-sulfotransferase3B1 (Heparansulfate D-glucosaminyl 3-O-sulfotransferase 3B1) (Heparansulfate3-O-sulfotransferase 3B1) (h3-OST-3B); (2504:) Heparan sulfateglucosamine 3-O-sulfotransferase 5 (Heparan sulfate D-glucosaminyl3-O-sulfotransferase 5) (Heparan sulfate3-O-sulfotransferase 5)(h3-OST-5); (2505:) Heparan sulfate glucosamine 3-O-sulfotransferase 6(Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 6) (Heparansulfate3-O-sulfotransferase 6) (h3-OST-6); (2506:) heparanase [Homosapiens]; (2507:) “Heparanase precursor (Heparanase-1) (Hpa1)(Endo-glucoronidase)[Contains:) Heparanase 8 kDa subunit; Heparanase 50kDa subunit].”; (2508:) heparanase precursor [Homo sapiens]; (2509:)Heparanase-2 (Hpa2); (2510:) Heparan-sulfate 6-O-sulfotransferase 1(HS6ST-1); (2511:) Heparan-sulfate 6-O-sulfotransferase 2 (HS6ST-2);(2512:) Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST-3); (2513:)Heparin-binding EGF-like growth factor precursor (HB-EGF) (HBEGF)(Diphtheria toxin receptor) (DT-R); (2514:) Hepatic triacylglycerollipase precursor (Hepatic lipase) (HL); (2515:) Hepatitis A viruscellular receptor 1 precursor (HAVcr-1) (T cell immunoglobulin and mucindomain-containing protein 1) (TIMD-1) (Tcell membrane protein 1) (TIM-1)(TIM); (2516:) Hepatocyte growth factor receptor precursor (HGFreceptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Metproto-oncogene tyrosine kinase) (c-Met); (2517:) Hepatocyte nuclearfactor 4-alpha (HNF-4-alpha) (Transcription factor HNF-4) (Transcriptionfactor 14); (2518:) Hepatocyte nuclear factor 4-gamma (HNF-4-gamma);(2519:) herpesvirus associated ubiquitin-specific protease (HAUSP) [Homosapiens]; (2520:) “HERV-K_(—)3q27.3 provirus ancestral Pol protein[Includes:) Reverse transcriptase (RT); Ribonuclease H(RNase H);Integrase (IN)].”; (2521:) HERV-K_(—)5q33.3 provirus ancestral Proprotein (HERV-K10 Pro protein) (HERV-K107 Pro protein) (Protease)(Proteinase) (PR); (2522:) “HERV-K_(—)7p22.1 provirus ancestral Polprotein (HERV-K(HML-2.HOM) Polprotein) (HERV-K₁₀₈ Pol protein)(HERV-K(C7) Pol protein)[Includes:) Reverse transcriptase (RT);Ribonuclease H(RNase H); Integrase (IN)].”; (2523:) heterogeneousnuclear ribonucleoprotein AB isoform a [Homo sapiens]; (2524:)heterogeneous nuclear ribonucleoprotein AB isoform b [Homo sapiens];(2525:) hexokinase 1 [Homo sapiens]; (2526:) hexokinase 1 isoform HKI[Homo sapiens]; (2527:) hexokinase 1 isoform HKI-R [Homo sapiens];(2528:) hexokinase 1 isoform HKI-ta/tb [Homo sapiens]; (2529:)hexokinase 1 isoform HKI-td [Homo sapiens]; (2530:) hexokinase 2 [Homosapiens]; (2531:) hexokinase 3 [Homo sapiens]; (2532:) Hexokinase-1(Hexokinase type 1) (HK I) (Brain form hexokinase); (2533:) Hexokinase-2(Hexokinase type II) (HK II) (Muscle form hexokinase); (2534:)Hexokinase-3 (Hexokinase type II) (HK III); (2535:) hexosaminidase Apreproprotein [Homo sapiens]; (2536:) hexosaminidase B preproprotein[Homo sapiens]; (2537:) hexose-6-phosphate dehydrogenase precursor [Homosapiens]; (2538:) HGD protein [Homo sapiens]; (2539:) “HHR6A (Humanhomologue of yeast RAD 6); putative.”; (2540:) “HHR6B (Human homologueof yeast RAD 6); putative.”; (2541:) High affinity immunoglobulinepsilon receptor alpha-subunit precursor (FcER1) (IgE Fc receptor,alpha-subunit) (Fc-epsilon RI-alpha); (2542:) High affinityimmunoglobulin epsilon receptor gamma-subunit precursor (FceRI gamma)(IgE Fc receptor gamma-subunit) (Fc-epsilon RI-gamma); (2543:) Highaffinity immunoglobulin epsilon receptor subunit beta (FcER1) (IgE Fcreceptor, subunit beta) (Fc epsilon receptor 1 beta-chain); (2544:)

High affinity immunoglobulin gamma Fc receptor I precursor (Fc-gamma RI)(FcRI) (IgG Fc receptor 1) (CD64 antigen); (2545:) High affinityinterleukin-8 receptor A (IL-8R A) (IL-8 receptor type 1) (CXCR-1)(CD181 antigen) (CDw128a); (2546:) High affinity interleukin-8 receptorB (IL-8R B) (CXCR-2) (GRO/MGSA receptor) (IL-8 receptor type 2) (CD182antigen) (CDw128b); (2547:) High affinity nerve growth factor receptorprecursor (Neurotrophictyrosine kinase receptor type 1) (TRK1transforming tyrosine kinase protein) (p140-TrkA) (Trk-A); (2548:)High-affinity cAMP-specific 3′,5′-cyclic phosphodiesterase 7A (HCP1)(TM22); (2549:) High-affinity cAMP-specific and IBMX-insensitive3′,5′-cyclic phosphodiesterase 8A; (2550:) High-affinity cAMP-specificand IBMX-insensitive 3′,5′-cyclic phosphodiesterase 8B (HSPDE8B);(2551:) High-affinity cationic amino acid transporter 1 (CAT-1) (CAT1)(System Y+ basic amino acid transporter) (Ecotropic retroviral leukemiareceptor homolog) (ERR) (Ecotropic retrovirus receptor homolog); (2552:)High-affinity cGMP-specific 3′,5′-cyclic phosphodiesterase 9A; (2553:)Histamine H1 receptor; (2554:) Histamine H2 receptor (H2R) (Gastricreceptor I); (2555:) Histamine H3 receptor (HH3R) (G-protein coupledreceptor 97); (2556:) Histamine H4 receptor (HH4R) (GPRv53) (G-proteincoupled receptor105) (GPCR105) (SP9144) (AXOR35); (2557:) HistamineN-methyltransferase (HMT); (2558:) histamine N-methyltransferase [Homosapiens]; (2559:) histamine N-methyltransferase isoform 1 [Homosapiens]; (2560:) histamine N-methyltransferase isoform 2 [Homosapiens]; (2561:) histamine N-methyltransferase isoform 3 [Homosapiens]; (2562:) histamine N-methyltransferase variant 1 [Homosapiens]; (2563:) histamine N-methyltransferase variant 2 [Homosapiens]; (2564:) histamine N-methyltransferase variant 3 [Homosapiens]; (2565:) histamine N-methyltransferase; (2566:) Histidine acidphosphatase domain containing 1 [Homo sapiens]; (2567:) Histidine acidphosphatase domain containing 2A isoform 4 [Homo sapiens]; (2568:)histidine ammonia-lyase [Homo sapiens]; (2569:) histidine decarboxylase[Homo sapiens]; (2570:) histidine triad nucleotide binding protein 1[Homo sapiens]; (2571:) histidine triad protein member 5 [Homo sapiens];(2572:) histidyl-tRNA synthetase [Homo sapiens]; (2573:) histidyl-tRNAsynthetase-like [Homo sapiens]; (2574:) Histone acetyltransferase HTATIP(60 kDa Tat interactive protein) (Tip60) (HIV-1 Tat interactive protein)(cPLA(2)-interacting protein); (2575:) Histone acetyltransferase MYST3(MYST protein 3) (MOZ, YBF2/SAS3, SAS2 and TIP60 protein 3)(Runt-related transcription factor-binding protein 2) (Monocyticleukemia zinc finger protein) (Zinc finger protein 220); (2576:) Histoneacetyltransferase MYST4 (MYST protein 4) (MOZ, YBF2/SAS3, SAS2 and TIP60protein 4) (Histone acetyltransferase MOZ2) (Monocytic leukemia zincfinger protein-related factor) (Histoneacetyltransferase MORF); (2577:)Histone acetyltransferase PCAF (P300/CBP-associated factor) (P/CAF)(Histone acetylase PCAF); (2578:) histone deacetylase 2 [Homo sapiens];(2579:) histone stem-loop binding protein [Homo sapiens]; (2580:)Histone-lysine N-methyltransferase, H3 lysine-79 specific (HistoneH3-K79 methyltransferase) (H3-K79-HMTase) (DOT1-like protein); (2581:)Histone-lysine N-methyltransferase, H3 lysine-9 specific 1 (HistoneH3-K9 methyltransferase 1) (H3-K9-HMTase 1) (Suppressor of variegation3-9 homolog 1) (Su(var)₃₋₉ homolog 1); (2582:) Histone-lysineN-methyltransferase, H3 lysine-9 specific 3 (Histone H3-K9methyltransferase 3) (H3-K9-HMTase 3) (Euchromatichistone-lysineN-methyltransferase 2) (HLA-B-associated transcript 8) (Protein G9a);(2583:) Histone-lysine N-methyltransferase, H3 lysine-9 specific 5(Histone H3-K9 methyltransferase 5) (H3-K9-HMTase 5)(Euchromatichistone-lysine N-methyltransferase 1) (Eu-HMTase 1)(G9a-like protein 1) (GLPI); (2584:) HIV-1 Tat interactive protein, 60kDa isoform 1 [Homo sapiens]; (2585:) HIV-1 Tat interactive protein, 60kDa isoform 2 [Homo sapiens]; (2586:) HIV-1 Tat interactive protein, 60kDa isoform 3 [Homo sapiens]; (2587:) HLA class II histocompatibilityantigen, DP alpha chain precursor (HLA-SB alpha chain) (MHC class IIDP3-alpha) (DP(W3)) (DP(W4)); (2588:) HLA-B associated transcript 8isoform a [Homo sapiens]; (2589:) HLA-B associated transcript 8 isoformb [Homo sapiens]; (2590:) hla-dcalpha alpha 2 domain (partial) [Homosapiens]; (2591:) hla-dralpha related alpha 2 domain [Homo sapiens];(2592:) HMC chymase I [Homo sapiens]; (2593:) HMGCR protein [Homosapiens]; (2594:) hMLH1 gene product; (2595:) HMT1 hnRNPmethyltransferase-like 6 [Homo sapiens]; (2596:) hMYHalpha1 [Homosapiens]; (2597:) hMYHalpha2 [Homo sapiens]; (2598:) hMYHalpha3 [Homosapiens]; (2599:) hMYHalpha4 [Homo sapiens]; (2600:) hMYHbeta1 [Homosapiens]; (2601:) hMYHbeta3 [Homo sapiens]; (2602:) hMYHbeta5 [Homosapiens]; (2603:) hMYHgamma2 [Homo sapiens]; (2604:) hMYHgamma3 [Homosapiens]; (2605:) hMYHgamma4 [Homo sapiens]; (2606:) HNF1-alphadimerization cofactor [Homo sapiens]; (2607:) homogentisate1,2-dioxygenase [Homo sapiens]; (2608:) “homogentisate 1,2-dioxygenase;HGO [Homo sapiens].”; (2609:) homogentisate dioxygenase [Homo sapiens];(2610:) homolgue of yeast DNA repair and recombination enzyme(RAD52)gene; (2611:) homolog of yeast long chain polyunsaturated fattyacid elongatio [Homo sapiens]; (2612:) homolog of yeast mutL gene;(2613:) Hormone-sensitive lipase (HSL); (2614:) hormone-sensitive lipase[Homo sapiens]; (2615:) HOYS7 [Homo sapiens]; (2616:) hPMS7 [Homosapiens]; (2617:) H-protein; (2618:) HSPC015 [Homo sapiens]; (2619:)HSPC140 [Homo sapiens]; (2620:) HSPC150 [Homo sapiens]; (2621:) HSPC153[Homo sapiens]; (2622:) HSPC279 [Homo sapiens]; (2623:) HtrA serinepeptidase 1 [Homo sapiens]; (2624:) human 26S proteasome subunit p97[Homo sapiens]; (2625:) Human Arylsulfatase A; (2626:) humanendothelin-converting enzyme-1d isoform [Homo sapiens]; (2627:) humangamma-glutamyl hydrolase [Homo sapiens]; (2628:) Human GlutathioneReductase A34e, R37w Mutant, Mixed Disulfide Between Trypanothione AndThe Enzyme; (2629:) Human Glutathione Reductase A34e, R37w Mutant,Oxidized Glutathione Complex; (2630:) Human Glutathione Reductase A34e,R37w Mutant, Oxidized Trypanothione Complex; (2631:) Human GlutathioneReductase A34e, R37w Mutant, Glutathionylspermidine Complex; (2632:)Human Glutathione Reductase A34eR37W MUTANT; (2633:) Human GlutathioneReductase Modified By Dinitrosoglutathione; (2634:) Human GlutathioneReductase Modified By Diglutathione-Dinitroso-lron; (2635:) humanhomolog of E. coli mutL gene product, Swiss-Prot Accession NumberP23367; (2636:) human mammary dihydrolipoamide acetyltransferase, maturesequence[Homo sapiens]; (2637:) Human Ubc9; (2638:) human ubiquitinconjugating enzyme G2 EC 6.3.2.19. [Homo sapiens]; (2639:) huntingtin[Homo sapiens]; (2640:) huntingtin interacting protein 2 [Homo sapiens];(2641:) huntingtin interacting protein; (2642:) hyaluronan synthase (EC2.4.1.-)—human; (2643:) hyaluronan synthase 3 [Homo sapiens]; (2644:)Hyaluronidase-2 precursor (Hyal-2) (Hyaluronoglucosaminidase-2)(LUCA-2); (2645:) hyaluronoglucosaminidase 1 isoform 1 [Homo sapiens];(2646:) hyaluronoglucosaminidase 1 isoform 2 [Homo sapiens]; (2647:)hyaluronoglucosaminidase 1 isoform 3 [Homo sapiens]; (2648:)hyaluronoglucosaminidase 1 isoform 4 [Homo sapiens]; (2649:)hyaluronoglucosaminidase 1 isoform 5 [Homo sapiens]; (2650:)hyaluronoglucosaminidase 1 isoform 6 [Homo sapiens]; (2651:) hydroxyacylglutathione hydrolase isoform 1 [Homo sapiens]; (2652:) hydroxyacylglutathione hydrolase isoform 2 [Homo sapiens]; (2653:)hydroxyacyl-Coenzyme A dehydrogenase, type II isoform 1 [Homo sapiens];(2654:) hydroxyacyl-Coenzyme A dehydrogenase, type II isoform 2 [Homosapiens]; (2655:) hydroxy-delta-5-steroid dehydrogenase, 3 beta- andsteroid delta-isomerase 1 [Homo sapiens]; (2656:)hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroiddelta-isomerase 2 [Homo sapiens]; (2657:) Hydroxymethylbilane synthase[Homo sapiens]; (2658:) hydroxymethylbilane synthase isoform 1 [Homosapiens]; (2659:) hydroxymethylbilane synthase isoform 2 [Homo sapiens];(2660:) hydroxymethylbilane synthase; (2661:) Hydroxymethylglutaryl-CoAsynthase, cytoplasmic (HMG-CoA synthase) (3-hydroxy-3-methylglutarylcoenzyme A synthase); (2662:) Hydroxymethylglutaryl-CoA synthase,mitochondrial precursor (HMG-CoA synthase) (3-hydroxy-3-methylglutarylcoenzyme A synthase); (2663:) hydroxyprostaglandin dehydrogenase15-(NAD) [Homo sapiens]; (2664:) hydroxysteroid (11-beta) dehydrogenase2 [Homo sapiens]; (2665:) hydroxysteroid (17-beta) dehydrogenase 1 [Homosapiens]; (2666:) hydroxysteroid (17-beta) dehydrogenase 2 [Homosapiens]; (2667:) hydroxysteroid (17-beta) dehydrogenase 4 [Homosapiens]; (2668:) hydroxysteroid (17-beta) dehydrogenase 7 [Homosapiens]; (2669:) hypoxanthine phosphoribosyltransferase [Homo sapiens];(2670:) hypoxanthine phosphoribosyltransferase 1 [Homo sapiens]; (2671:)Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (HGPRTase);(2672:) Hypoxia-inducible factor 1 alpha (HIF-1 alpha) (HIF1 alpha)(ARNT-interacting protein) (Member of PAS protein 1) (MOP1); (2673:)Hypoxia-inducible factor 1 alpha inhibitor (Hypoxia-inducible factorasparagine hydroxylase) (Factor inhibiting HIF-1) (FIH-1); (2674:)hypoxia-inducible factor 1, alpha subunit inhibitor [Homo sapiens];(2675:) hypoxia-inducible factor 1, alpha subunit isoform 1 [Homosapiens]; (2676:) hypoxia-inducible factor 1, alpha subunit isoform 2[Homo sapiens]; (2677:) 1 beta 1-6 N-acetylglucosaminyltransferase;(2678:) 1 beta-1,6-N-acetylglucosaminyltransferase A form [Homosapiens]; (2679:) 1 beta-1,6-N-acetylglucosaminyltransferase B form[Homo sapiens]; (2680:) 1 beta-1,6-N-acetylglucosaminyltransferase Cform [Homo sapiens]; (2681:) IARS2 protein [Homo sapiens]; (2682:)“i-beta-1,3-N-acetylglucosaminyltransferase; poly-N-acetyllactosamineextension enzyme i-antigen; iGnT [Homo sapiens].”; (2683:) 1-branchingbeta-1,6-acetylglucosaminyltransferase family polypeptide 1 [Homosapiens]; (2684:) I-branching beta-1,6-acetylglucosaminyltransferasefamily polypeptide 2 [Homo sapiens]; (2685:) I-branchingbeta-1,6-acetylglucosaminyltransferase family polypeptide 3 [Homosapiens]; (2686:) 1-branching enzyme [Homo sapiens]; (2687:)ICE-LAP6—human; (2688:) ICE-LAP6; (2689:) ICH-1L; (2690:) ICH-1S;(2691:) lch-2; (2692:) “Iduronate 2-sulfatase precursor(Alpha-L-iduronate sulfatesulfatase) (Idursulfase) [Contains:) Iduronate2-sulfatase 42 kDa chain; Iduronate 2-sulfatase 14 kDa chain].”; (2693:)iduronate 2-sulfatase; (2694:) I-FLICE [Homo sapiens]; (2695:) I-FLICEisoform 2 [Homo sapiens]; (2696:) I-FLICE isoform 3 [Homo sapiens];(2697:) I-FLICE isoform 4 [Homo sapiens]; (2698:) I-FLICE isoform 5[Homo sapiens]; (2699:) IgG receptor FcRn large subunit p51 precursor(FcRn) (Neonatal Fc receptor) (IgG Fc fragment receptor transporter,alpha chain); (2700:) IKK-related kinase epsilon [Homo sapiens]; (2701:)IIvB (bacterial acetolactate synthase)-like [Homo sapiens]; (2702:) ilvB(bacterial acetolactate synthase)-like isoform 1 [Homo sapiens]; (2703:)ilvB (bacterial acetolactate synthase)-like isoform 1 variant [Homosapiens]; (2704:) ilvB (bacterial acetolactate synthase)-like isoform 2[Homo sapiens]; (2705:) immunodeficiency virus type 1, HIV-1 gp120—human(fragments); (2706:) Immunoglobulin alpha Fc receptor precursor (IgA Fcreceptor) (CD89antigen); (2707:) Immunoglobulin-like domain-containingreceptor 1 precursor; (2708:) Importin-11 (Imp 11) (Ran-binding protein11) (RanBP11); (2709:) Inactive ubiquitin carboxyl-terminal hydrolase 50(Inactive ubiquitin-specific peptidase 50); (2710:) indoleamine-pyrrole2,3 dioxygenase [Homo sapiens]; (2711:) indolethylamineN-methyltransferase [Homo sapiens]; (2712:) inducible nitric oxidesynthase; (2713:) inhibin alpha subunit precursor [Homo sapiens];(2714:) inhibin beta A precursor [Homo sapiens]; (2715:) inhibin beta Bsubunit precursor [Homo sapiens]; (2716:) inhibitor of kappa lightpolypeptide gene enhancer in B-cells, kinase beta [Homo sapiens];(2717:) inhibitor of kappa light polypeptide gene enhancer in B-cells,kinase gamma [Homo sapiens]; (2718:) Inhibitor of nuclear factor kappa-Bkinase alpha subunit (I kappa-B kinase alpha) (IkBKA) (IKK-alpha)(IKK-A) (IkappaB kinase) (1-kappa-B kinase 1) (IKK1) (Conservedhelix-loop-helix ubiquitous kinase) (Nuclear factor NF-kappa-B inhibitorkinase alpha) (NFKBIKA); (2719:) Inner Lipoyl Domain From Human PyruvateDehydrogenase (Pdh) Complex, Nmr, 1 Structure; (2720:) Inorganicpyrophosphatase (Pyrophosphate phospho-hydrolase) (PPase); (2721:)Inorganic pyrophosphatase 2, mitochondrial precursor (PPase 2)(Pyrophosphatase SID6-306); (2722:) inosine monophosphate dehydrogenase2 [Homo sapiens]; (2723:) Inosine triphosphate pyrophosphatase (ITPase)(Inosine triphosphatase) (Putative oncogene protein hlc14-06-p); (2724:)Inosine-5′-monophosphate dehydrogenase 1 (IMP dehydrogenase 1) (IMPDH-I)(IMPD 1); (2725:) Inosine-5′-monophosphate dehydrogenase 2 (IMPdehydrogenase 2) (IMPDH-II) (IMPD 2); (2726:) inositol1,3,4,5,6-pentakisphosphate 2-kinase [Homo sapiens]; (2727:) inositol1,3,4-triphosphate 5/6 kinase [Homo sapiens]; (2728:) inositol1,3,4-trisphosphate 5/6-kinase; (2729:) inositol 1,4,5-triphosphatereceptor, type 3 [Homo sapiens]; (2730:) inositol 1,4,5-trisphosphate3-kinase B—human; (2731:) Inositol 1,4,5-trisphosphate receptor type 1(Type 1 inositol 1,4,5-trisphosphate receptor) (Type 1 InsP3 receptor)(IP3 receptor isoform 1) (InsP3R1) (IP3R); (2732:) Inositol1,4,5-trisphosphate receptor type 2 (Type 2 inositol 1,4,5-trisphosphatereceptor) (Type 2 InsP3 receptor) (IP3 receptor isoform 2) (InsP3R2);(2733:) Inositol 1,4,5-trisphosphate receptor type 3 (Type 3 inositol1,4,5-trisphosphate receptor) (Type 3 InsP3 receptor) (IP3 receptorisoform 3) (InsP3R3); (2734:) Inositol Monophosphatase (E.C.3.1.3.25)(Apoenzyme); (2735:) Inositol monophosphatase (IMPase) (IMP)(Inositol-1(or 4)-monophosphatase) (Lithium-sensitive myo-inositolmonophosphatase A1); (2736:) Inositol monophosphatase 2 (IMPase 2) (IMP2) (Inositol-1(or 4)-monophosphatase 2) (Myo-inositol monophosphataseA2); (2737:) Inositol polyphosphate 1-phosphatase (IPPase) (IPP);(2738:) inositol polyphosphate-1-phosphatase [Homo sapiens]; (2739:)inositol polyphosphate-4-phosphatase, type 1 isoform a [Homo sapiens];(2740:) inositol polyphosphate-4-phosphatase, type 1 isoform b [Homosapiens]; (2741:) inositol polyphosphate-4-phosphatase, type II, 105 kD[Homo sapiens]; (2742:) inositol(myo)-1(or 4)-monophosphatase 1 [Homosapiens]; (2743:) Inositol-pentakisphosphate 2-kinase(Inositol-1,3,4,5,6-pentakisphosphate 2-kinase)(Ins(1,3,4,5,6)P52-kinase) (InsP5 2-kinase) (IPK1 homolog); (2744:)Inositol-tetrakisphosphate 1-kinase (Inositol-triphosphate 5/6-kinase)(Inositol 1,3,4-trisphosphate 5/6-kinase); (2745:)Inositol-trisphosphate 3-kinase A (Inositol 1,4,5-trisphosphate 3-kinaseA) (IP3K A) (IP3 3-kinase A); (2746:) Inositol-trisphosphate 3-kinase B(Inositol 1,4,5-trisphosphate 3-kinase B) (IP3K B) (IP3 3-kinase B)(IP3K-B); (2747:) Inositol-trisphosphate 3-kinase C (Inositol1,4,5-trisphosphate 3-kinase C) (InsP 3-kinase C) (IP3K-C); (2748:)insulin receptor [Homo sapiens]; (2749:) “Insulin receptor precursor(1R) (CD220 antigen) [Contains:) Insulin receptor subunit alpha; Insulinreceptor subunit beta].”; (2750:) insulin receptor substrate 1 [Homosapiens]; (2751:) “Insulin receptor-related protein precursor (IRR)(IR-related receptor) [Contains:) Insulin receptor-related protein alphachain; Insulin receptor-related protein beta chain].”; (2752:) insulinreceptor-related receptor—human (fragment); (2753:) Insulin-degradingenzyme (Insulysin) (Insulinase) (Insulin protease); (2754:)Insulin-degrading enzyme [Homo sapiens]; (2755:) insulin-like growthfactor 1 (somatomedin C) [Homo sapiens]; (2756:) “Insulin-like growthfactor 1 receptor precursor (Insulin-like growth factor I receptor)(IGF-I receptor) (CD221 antigen)[Contains:) Insulin-like growth factor 1receptor alpha chain; Insulin-like growth factor 1 receptor betachain].”; (2757:) insulin-like growth factor 2 [Homo sapiens]; (2758:)insulin-like growth factor 2 receptor [Homo sapiens]; (2759:) insulysin[Homo sapiens]; (2760:) Integral membrane protein 2B (Transmembraneprotein BRI) [Contains:ABri/ADan amyloid peptide]; (2761:) Integralmembrane protein 2C (Transmembrane protein BRI3) (Cerebral protein 14)[Contains:) CT-BRI3]; (2762:) integral membrane protein 2C isoform 1[Homo sapiens]; (2763:) integral membrane protein 2C isoform 2 [Homosapiens]; (2764:) integral membrane protein 2C isoform 3 [Homo sapiens];(2765:) Integral membrane protein DGCR2/IDD precursor; (2766:) integrinalpha chain, alpha 6 [Homo sapiens]; (2767:) Integrin alpha-1 (Lamininand collagen receptor) (VLA-1) (CD49a antigen); (2768:) Integrinalpha-10 precursor; (2769:) Integrin alpha-11 precursor; (2770:)Integrin alpha-2 precursor (Platelet membrane glycoprotein Ia) (GPIa)(Collagen receptor) (VLA-2 alpha chain) (CD49b antigen); (2771:)“Integrin alpha-3 precursor (Galactoprotein B3) (GAPB3) (VLA-3 alphachain) (FRP-2) (CD49c antigen) [Contains:) Integrin alpha-3 heavy chain;Integrin alpha-3 light chain].”; (2772:) Integrin alpha-4 precursor(Integrin alpha-IV) (VLA-4) (CD49d antigen); (2773:) “Integrin alpha-5precursor (Fibronectin receptor subunit alpha) (Integrin alpha-F)(VLA-5) (CD49e antigen) [Contains:) Integrin alpha-5 heavy chain;Integrin alpha-5 light chain].”; (2774:) “Integrin alpha-6 precursor(VLA-6) (CD49f antigen) [Contains:Integrin alpha-6 heavy chain; Integrinalpha-6 light chain].”; (2775:) “Integrin alpha-7 precursor [Contains:)Integrin alpha-7 heavy chain; Integrin alpha-7 light chain].”; (2776:)“Integrin alpha-8 precursor [Contains:) Integrin alpha-8 heavy chain;Integrin alpha-8 light chain].”; (2777:) Integrin alpha-9 precursor(Integrin alpha-RLC); (2778:) Integrin alpha-D precursor (Leukointegrinalpha D) (ADB2) (CD11d antigen); (2779:) “Integrin alpha-E precursor(Mucosal lymphocyte 1 antigen) (HML-1 antigen) (Integrin alpha-IEL)(CD103 antigen) [Contains:) Integrin alpha-E light chain; Integrinalpha-E heavy chain].”; (2780:) “Integrin alpha-11b precursor (Plateletmembrane glycoprotein IIb) (GPalpha IIb) (GPIIb) (CD41 antigen)[Contains:) Integrin alpha-IIb heavy chain; Integrin alpha-IIb lightchain].”; (2781:) Integrin alpha-L precursor (Leukocyte adhesionglycoprotein LFA-1 alpha chain) (LFA-1A) (Leukocyte function-associatedmolecule 1alpha chain) (CD1a antigen); (2782:) Integrin alpha-Mprecursor (Cell surface glycoprotein MAC-1 alpha subunit) (CR-3 alphachain) (Leukocyte adhesion receptor MO) (Neutrophil adherence receptor)(CD11b antigen); (2783:) “Integrin alpha-V precursor (Vitronectinreceptor subunit alpha) (CD51 antigen) [Contains:) Integrin alpha-Vheavy chain; Integrin alpha-V light chain].”; (2784:) Integrin alpha-Xprecursor (Leukocyte adhesion glycoprotein p150,95alpha chain)(Leukocyte adhesion receptor p150,95) (Leu M5) (CD11c antigen); (2785:)Integrin beta 1 binding protein 3 [Homo sapiens]; (2786:) integrin beta1 binding protein 3 isoform 2 [Homo sapiens]; (2787:) Integrin beta-1precursor (Fibronectin receptor subunit beta) (Integrin VLA-4 subunitbeta) (CD29 antigen); (2788:) Integrin beta-2 precursor (Cell surfaceadhesion glycoproteins LFA-1/CR3/p150,95 subunit beta) (Complementreceptor C3 subunit beta) (CD18 antigen); (2789:) Integrin beta-3precursor (Platelet membrane glycoprotein IIIa) (GPIIIa) (CD61 antigen);(2790:) Integrin beta-4 precursor (GP150) (CD104 antigen); (2791:)Integrin beta-5 precursor; (2792:) Integrin beta-6 precursor; (2793:)Integrin beta-7 precursor; (2794:) integrin beta-8 precursor; (2795:)integrin-linked kinase [Homo sapiens]; (2796:) Integrin-linked proteinkinase 1 (ILK-1) (59 kDa serine/threonine-protein kinase) (p591LK);(2797:) inter-alpha globulin inhibitor H2 polypeptide [Homo sapiens];(2798:) intercellular adhesion molecule 1 precursor [Homo sapiens];(2799:) interferon, gamma [Homo sapiens]; (2800:) interferon,gamma-inducible protein 30 preproprotein [Homo sapiens]; (2801:)Interferon-alpha/beta receptor alpha chain precursor (IFN-alpha-REC);(2802:) Interferon-alpha/beta receptor beta chain precursor(IFN-alpha-REC) (Type I interferon receptor) (IFN-R) (Interferonalpha/beta receptor 2); (2803:) Interferon-gamma receptor alpha chainprecursor (IFN-gamma-R1) (CD119 antigen) (CDw119); (2804:)Interferon-gamma receptor beta chain precursor (Interferon-gammareceptor accessory factor 1) (AF-1) (Interferon-gamma transducer 1);(2805:) Interferon-induced 17 kDa protein precursor [Contains:)Ubiquitin cross-reactive protein (hUCRP) (Interferon-induced 15 kDaprotein)]; (2806:) Interferon-induced, double-stranded RNA-activatedprotein kinase (Interferon-inducible RNA-dependent protein kinase)(Protein kinase RNA-activated) (PKR) (p68 kinase) (P1/eIF-2A proteinkinase); (2807:) Interferon-stimulated gene 20 kDa protein(Promyelocytic leukemia nuclear body-associated protein ISG20)(Estrogen-regulated transcript 45 protein); (2808:) interleukin 1receptor antagonist isoform 1 precursor [Homo sapiens]; (2809:)interleukin 1 receptor antagonist isoform 2 [Homo sapiens]; (2810:)interleukin 1 receptor antagonist isoform 3 [Homo sapiens]; (2811:)interleukin 1 receptor antagonist isoform 4 [Homo sapiens]; (2812:)interleukin 1, beta proprotein [Homo sapiens]; (2813:) interleukin 18proprotein [Homo sapiens]; (2814:) interleukin 1-beta convertase [Homosapiens]; (2815:) interleukin 1-beta convertase; (2816:) Interleukin1-beta converting enzyme isoform beta; (2817:) Interleukin 1-betaconverting enzyme isoform delta; (2818:) Interleukin 1-beta convertingenzyme isoform epsilon; (2819:) interleukin 1-beta converting enzymeisoform gamma; (2820:) interleukin 1 beta-converting enzyme; (2821:)interleukin 6 receptor isoform 1 precursor [Homo sapiens]; (2822:)interleukin 6 receptor isoform 2 precursor [Homo sapiens]; (2823:)interleukin 8 precursor [Homo sapiens]; (2824:) interleukin 8 receptorbeta [Homo sapiens]; (2825:) interleukin-1 beta converting enzyme{N-terminal} [human, Peptide Partial, 23 aa]; (2826:) Interleukin-1receptor accessory protein precursor (IL-1 receptor accessory protein)(IL-1 RAcP); (2827:) Interleukin-1 receptor type I precursor (IL-1R-1)(IL-1RT1) (IL-1R-alpha) (p80) (CD121a antigen); (2828:) Interleukin-1receptor type II precursor (IL-1R-2) (IL-1R-beta) (CD121b antigen)(CDw121b); (2829:) Interleukin-1 receptor-associated kinase 1 (IRAK-1);(2830:) Interleukin-1 receptor-associated kinase-like 2 (IRAK-2);(2831:) Interleukin-1 receptor-like 1 precursor (ST2 protein); (2832:)Interleukin-1 receptor-like 2 precursor (IL-1Rrp2) (Interleukin-1receptor-related protein 2) (IL1R-rp2); (2833:) Interleukin-10 receptoralpha chain precursor (IL-10R-A) (IL-10R1) (CDw210a antigen); (2834:)Interleukin-10 receptor beta chain precursor (IL-10R-B) (IL-10R2)(Cytokine receptor family 2 member 4) (Cytokine receptor class-II member4) (CRF2-4) (CDw210b antigen); (2835:) Interleukin-11 receptor alphachain precursor (IL-11R-alpha) (IL-11RA); (2836:) Interleukin-12receptor beta-1 chain precursor (IL-12R-beta1) (Interleukin-12 receptorbeta) (IL-12 receptor beta component) (IL-12RB1) (CD212 antigen);(2837:) Interleukin-12 receptor beta-2 chain precursor (IL-12 receptorbeta-2) (IL-12R-beta2); (2838:) Interleukin-13 receptor alpha-1 chainprecursor (IL-13R-alpha-1) (IL-13RA-1) (CD213a1 antigen); (2839:)Interleukin-13 receptor alpha-2 chain precursor (Interleukin-1,3-bindingprotein) (CD213a2 antigen); (2840:) Interleukin-15 receptor alpha chainprecursor (IL-15R-alpha) (IL-15RA); (2841:) Interleukin-17 receptor Aprecursor (IL-17 receptor) (CD217antigen) (CDw217); (2842:)Interleukin-17 receptor B precursor (IL-17 receptor B) (IL-17RB)(Interleukin-17B receptor) (IL-17B receptor) (IL-17 receptor homolog 1)(IL-17Rh1) (IL17Rh1) (Cytokine receptor CRL4); (2843:) Interleukin-17receptor C precursor (IL-17 receptor C) (IL-17RC) (Interleukin-17receptor-like protein) (IL-17RL) (Interleukin-17receptor homolog)(IL17Rhom); (2844:) Interleukin-17 receptor D precursor (IL-17 receptorD) (IL-17RD) (Interleukin-17D receptor) (IL-17D receptor) (IL17Rhom)(Interleukin-17 receptor-like protein) (Sef homolog) (hSef); (2845:)Interleukin-18 receptor 1 precursor (IL1 receptor-related protein)(IL-1Rrp) (CDw218a antigen); (2846:) Interleukin-18 receptor accessoryprotein precursor (IL-18 receptor accessory protein) (IL-18RAcP)(Interleukin-18 receptor accessory protein-like) (IL-18Rbeta) (IL-1Raccessory protein-like) (IL-1RAcPL) (Accessory protein-like) (AcPL)(IL-1R7) (CDw218b antigen); (2847:) interleukin-1B converting enzyme[Homo sapiens]; (2848:) Interleukin-2 receptor alpha chain precursor(IL-2 receptor alpha subunit) (IL-2-RA) (IL2-RA) (p55) (TAC antigen)(CD25 antigen); (2849:) Interleukin-2 receptor subunit beta precursor(IL-2 receptor) (P70-75) (p75) (High affinity IL-2 receptor subunitbeta) (CD122antigen); (2850:) Interleukin-20 receptor alpha chainprecursor (IL-20R-alpha) (IL-20R1) (Cytokine receptor family 2 member 8)(Cytokine receptor class-II member 8) (CRF2-8) (ZcytoR7); (2851:)Interleukin-20 receptor beta chain precursor (IL-20R-beta) (IL-20R2);(2852:) Interleukin-21 receptor precursor (IL-21R) (Novel interleukinreceptor); (2853:) Interleukin-22 receptor alpha-2 chain precursor(IL-22R-alpha-2) (Interleukin 22-binding protein) (IL22BP) (Cytokinereceptor family class II member 10) (CRF2-10) (Cytokine receptor familytype 2, soluble 1) (CRF2-S1); (2854:) Interleukin-27 receptor alphachain precursor (IL-27R-alpha) (WSX-1) (Type I T-cell cytokine receptor)(TCCR) (Protein CRL1); (2855:) Interleukin-28 receptor alpha chainprecursor (IL-28R-alpha) (IL-28RA) (Cytokine receptor family 2 member12) (Cytokine receptor class-II member 12) (CRF2-12) (Interferon lambdareceptor 1) (IFN-lambda R1) (Likely interleukin or cytokine receptor 2);(2856:) Interleukin-3 receptor alpha chain precursor (IL-3R-alpha)(CD123antigen); (2857:) Interleukin-4 receptor alpha chain precursor(IL-4R-alpha) (CD124antigen) [Contains:) Soluble interleukin-4 receptoralpha chain (sIL4R alpha/prot) (IL-4-binding protein) (IL4-BP)]; (2858:)Interleukin-5 receptor alpha chain precursor (IL-5R-alpha)(CD125antigen) (CDw125); (2859:) Interleukin-6 receptor alpha chainprecursor (IL-6R-alpha) (IL-6R1) (Membrane glycoprotein 80) (gp80)(CD126 antigen); (2860:) Interleukin-6 receptor subunit beta precursor(IL-6R-beta) (Interleukin-6 signal transducer) (Membrane glycoprotein130) (gp130) (Oncostatin-M receptor alpha subunit) (CD130 antigen)(CDw130); (2861:) Interleukin-7 receptor alpha chain precursor(IL-7R-alpha) (CD127antigen) (CDw127); (2862:) Interleukin-9 receptorprecursor (IL-9R) (CD129 antigen); (2863:) Interphotoreceptor matrixproteoglycan 1 precursor (Interphotoreceptor matrix proteoglycan of 150kDa) (IPM-150) (Sialoprotein associated with cones and rods); (2864:)“Interstitial collagenase precursor (Matrix metalloproteinase-1) (MMP-1)(Fibroblast collagenase) [Contains:) 22 kDa interstitial collagenase; 27kDa interstitial collagenase].”; (2865:) intestinal alkaline phosphataseprecursor [Homo sapiens]; (2866:) intestinal alkaline sphingomyelinase[Homo sapiens]; (2867:) iron-sulfur cluster assembly enzyme isoformISCU1 [Homo sapiens]; (2868:) iron-sulfur cluster assembly enzymeisoform ISCU2 precursor [Homo sapiens]; (2869:) islet amyloidpolypeptide precursor [Homo sapiens]; (2870:) Isocitrate dehydrogenase[NAD] subunit gamma, mitochondrial precursor (Isocitric dehydrogenase)(NAD(+)-specific ICDH); (2871:) Isocitrate dehydrogenase [NADP]cytoplasmic (Cytosolic NADP-isocitrate dehydrogenase) (Oxalosuccinatedecarboxylase) (IDH) (NADP(+)-specific ICDH) (IDP); (2872:) isocitratedehydrogenase 1 (NADP+), soluble [Homo sapiens]; (2873:) isocitratedehydrogenase 3 (NAD+) alpha precursor [Homo sapiens]; (2874:)isopentenyl-diphosphate delta isomerase [Homo sapiens]; (2875:)isopeptidase T; (2876:) isopeptidase T-3 [Homo sapiens]; (2877:)isoprenylcysteine carboxyl methyltransferase [Homo sapiens]; (2878:)isovaleryl Coenzyme A dehydrogenase [Homo sapiens]; (2879:) Itchyhomolog E3 ubiquitin protein ligase (Itch) (Atrophin-1-interactingprotein 4) (AIP4) (NFE2-associated polypeptide 1) (NAPP1); (2880:) Januskinase 3 [Homo sapiens]; (2881:) JmjC domain-containing histonedemethylation protein 1B([Histone-H3]-lysine-36 demethylase 1B)(F-box/LRR-repeat protein10) (F-box and leucine-rich repeat protein 10)(F-box protein FBL10) (Protein JEMMA) (Jumonji domain-containingEMSY-interactormethyltransferase motif protein) (CXXC-type zinc fingerprotein 2) (Protein-containing CXXC domain 2); (2882:) JmjCdomain-containing histone demethylation protein 2B (Jumonjidomain-containing protein 1B) (Nuclear protein 5qNCA); (2883:) JmjCdomain-containing histone demethylation protein 3B (Jumonjidomain-containing protein 2B); (2884:) JmjC domain-containing histonedemethylation protein 3C (Jumonji domain-containing protein 2C) (Geneamplified in squamous cell carcinoma 1 protein) (GASC-1 protein);(2885:) JmjC domain-containing histone demethylation protein 3D (Jumonjidomain-containing protein 2D); (2886:) JRK protein [Homo sapiens];(2887:) jub, ajuba homolog isoform 1 [Homo sapiens]; (2888:) jub, ajubahomolog isoform 2 [Homo sapiens]; (2889:) jun oncogene [Homo sapiens];(2890:) junction plakoglobin [Homo sapiens]; (2891:) JUP protein [Homosapiens]; (2892:) kalirin, RhoGEF kinase isoform 1 [Homo sapiens];(2893:) kalirin, RhoGEF kinase isoform 2 [Homo sapiens]; (2894:)kalirin, RhoGEF kinase isoform 3 [Homo sapiens]; (2895:) kallikrein 8isoform 1 preproprotein [Homo sapiens]; (2896:) kallikrein 8 isoform 2[Homo sapiens]; (2897:) kallikrein 8 isoform 3 [Homo sapiens]; (2898:)kallikrein 8 isoform 4 [Homo sapiens]; (2899:) Kallikrein-5 precursor(Stratum corneum tryptic enzyme) (Kallikrein-like protein 2) (KLK-L2);(2900:) Kallikrein-6 precursor (Protease M) (Neurosin) (Zyme) (SP59);(2901:) Kallikrein-7 precursor (hK7) (Stratum corneum chymotrypticenzyme) (hSCCE); (2902:) kallikrein-related peptidase 4 preproprotein[Homo sapiens]; (2903:) kallikrein-related peptidase 5 preproprotein[Homo sapiens]; (2904:) kallikrein-related peptidase 6 isoform Apreproprotein [Homo sapiens]; (2905:) kallikrein-related peptidase 6isoform B [Homo sapiens]; (2906:) Kallistatin precursor (Serpin A4)(Kallikrein inhibitor) (Protease inhibitor 4); (2907:) Kappa-type opioidreceptor (KOR-1); (2908:) KAT3 protein [Homo sapiens]; (2909:) Kataninp60 ATPase-containing subunit A1 (Katanin p60 subunit A1) (p60 katanin);(2910:) katanin p60 subunit A 1 [Homo sapiens]; (2911:) katanin p80subunit B1 [Homo sapiens]; (2912:) KDEL (Lys-Asp-Glu-Leu) containing 1[Homo sapiens]; (2913:) KDEL (Lys-Asp-Glu-Leu) containing 2 [Homosapiens]; (2914:) KDEL motif-containing protein 1 precursor; (2915:)KDEL motif-containing protein 2 precursor; (2916:) Kelch-likeECH-associated protein 1 (Cytosolic inhibitor of Nrf2) (Kelch-likeprotein 19); (2917:) Kell blood group, metallo-endopeptidase [Homosapiens]; (2918:) keratan sulfate Gal-6-sulfotransferase [Homo sapiens];(2919:) Ketohexokinase (Hepatic fructokinase); (2920:)Ketosamine-3-kinase (Fructosamine-3-kinase-related protein); (2921:)KH-type splicing regulatory protein (FUSE binding protein 2) [Homosapiens]; (2922:) kidney and liver proline oxidase 1 [Homo sapiens];(2923:) Killer cell immunoglobulin-like receptor 2DL1 precursor (MHCclass I NK cell receptor) (Natural killer-associated transcript 1)(NKAT-1) (p58 natural killer cell receptor clones CL-42/47.11) (p58NKreceptor) (p58.1 MHC class-I-specific NK receptor) (CD158a antigen);(2924:) Killer cell immunoglobulin-like receptor 2DL2 precursor (MHCclass I NK cell receptor) (Natural killer-associated transcript 6)(NKAT-6) (p58 natural killer cell receptor clone CL-43) (p58 NKreceptor); (2925:) Killer cell immunoglobulin-like receptor 2DL3precursor (MHC class I NK cell receptor) (Natural killer-associatedtranscript 2) (NKAT-2) (NKAT2a) (NKAT2b) (p58 natural killer cellreceptor clone CL-6) (p58 NK receptor) (p58.2 MHC class-1-specific NKreceptor) (Killer inhibitory receptor cl 2-3) (KIR-023 GB) (CD158bantigen); (2926:) Killer cell immunoglobulin-like receptor 2DL4precursor (MHC class I NK cell receptor KIR103AS) (Killer cellinhibitory receptor103AS) (KIR-103AS) (G9P) (CD158d antigen); (2927:)Killer cell immunoglobulin-like receptor 2DSI precursor (MHC class I NKcell receptor Eb6 ActI) (CD158h antigen); (2928:) Killer cellimmunoglobulin-like receptor 2DS2 precursor (MHC class I NK cellreceptor) (Natural killer-associated transcript 5) (NKAT-5) (p58 naturalkiller cell receptor clone CL-49) (p58 NK receptor) (NK receptor 183ActI) (CD158j antigen); (2929:) Killer cell immunoglobulin-like receptor2DS3 precursor (MHC class I NK cell receptor) (Natural killer-associatedtranscript 7) (NKAT-7); (2930:) Killer cell immunoglobulin-like receptor2DS4 precursor (MHC class I NK cell receptor) (Natural killer-associatedtranscript 8) (NKAT-8) (P58 natural killer cell receptor clone CL-39)(p58 NK receptor) (CL-17) (CD158i antigen); (2931:) Killer cellimmunoglobulin-like receptor 2DS5 precursor (MHC class I NK cellreceptor) (Natural killer-associated transcript 9) (NKAT-9) (CD158gantigen); (2932:) Killer cell immunoglobulin-like receptor 3DL1precursor (MHC class I NK cell receptor) (Natural killer-associatedtranscript 3) (NKAT-3) (p70 natural killer cell receptor clonesCL-2/CL-11) (HLA-BW4-specific inhibitory NK cell receptor); (2933:)Killer cell immunoglobulin-like receptor 3DL2 precursor (MHC class I NKcell receptor) (Natural killer-associated transcript 4) (NKAT-4) (p70natural killer cell receptor clone CL-5) (CD158k antigen); (2934:)Killer cell immunoglobulin-like receptor 3DL3 precursor (Killer cellinhibitory receptor 1) (CD158z antigen); (2935:) Killer cellimmunoglobulin-like receptor 3DS1 precursor (MHC class I NK cellreceptor) (Natural killer-associated transcript 10) (NKAT-10); (2936:)Killer cell lectin-like receptor subfamily F member 1 (Lectin-likereceptor F1) (Activating coreceptor NKp80); (2937:) kinase insert domainreceptor (a type III receptor tyrosine kinase)[Homo sapiens]; (2938:)kinase interacting stathmin [Homo sapiens]; (2939:) kinase relatedprotein, telokin isoform 7 [Homo sapiens]; (2940:) kinase relatedprotein, telokin isoform 8 [Homo sapiens]; (2941:) kinase,phosphoglycerate; (2942:) kinesin family member 23 isoform 1 [Homosapiens]; (2943:) kinesin family member 23 isoform 2 [Homo sapiens];(2944:) Kinesin-like protein KIF23 (Mitotic kinesin-like protein 1)(Kinesin-like protein 5); (2945:) Kinesin-like protein KIFC1(Kinesin-like protein 2) (Kinesin-related protein HSET); (2946:) KiSS-1receptor (KiSS-1R) (Kisspeptins receptor) (Metastin receptor) (G-proteincoupled receptor 54) (Hypogonadotropin-1) (hOT7T175); (2947:) KIAA0184[Homo sapiens]; (2948:) KIAA0184 protein [Homo sapiens]; (2949:) KIM0377splice variant 4 [Homo sapiens]; (2950:) KIAA0398 [Homo sapiens];(2951:) KIAA0433 [Homo sapiens]; (2952:) KIAA0837 protein [Homosapiens]; (2953:) KIM0934 protein [Homo sapiens]; (2954:) KIAA1238protein [Homo sapiens]; (2955:) KIAA1289 protein [Homo sapiens]; (2956:)KIAA1385 protein [Homo sapiens]; (2957:) KIM1463 protein [Homo sapiens];(2958:) KIAA1516 protein [Homo sapiens]; (2959:) KIAA1734 protein [Homosapiens]; (2960:) KIAA1846 protein [Homo sapiens]; (2961:) KIAA1963protein [Homo sapiens]; (2962:) KIAA1992 protein [Homo sapiens]; (2963:)Kruppel-like factor 4 (gut) [Homo sapiens]; (2964:) kynureninase(L-kynurenine hydrolase) isoform a [Homo sapiens]; (2965:) kynureninase(L-kynurenine hydrolase) isoform b [Homo sapiens]; (2966:) Kynureninase(L-kynurenine hydrolase); (2967:) Kynurenine 3-monooxygenase (Kynurenine3-hydroxylase); (2968:) kynurenine aminotransferase III [Homo sapiens];(2969:) kynurenine aminotransferase III isoform 1 [Homo sapiens];(2970:) kynurenine aminotransferase III isoform 2 [Homo sapiens];(2971:) L-3-hydroxyacyl-Coenzyme A dehydrogenase precursor [Homosapiens]; (2972:) “Lactase-phlorizin hydrolase precursor(Lactase-glycosylceramidase)[Includes:) Lactase; Phlorizin hydrolase].”;(2973:) lactase-phlorizin hydrolase preproprotein [Homo sapiens];(2974:) lactate dehydrogenase A [Homo sapiens]; (2975:) Lactosylceramide4-alpha-galactosyltransferase (Alpha-1,4-galactosyltransferase)(UDP-galactose:beta-D-galactosyl-beta1-R4-alpha-D-galactosyltransferase)(Alpha-1,4-N-acetylglucosaminyltransferase) (Alpha4Gal-T1)(Globotriaosylceramide synthase) (Gb3 synthase) (CD77 synthase) (P1/Pksynthase); (2976:) Lactoylglutathione lyase (Methylglyoxalase)(Aldoketomutase) (Glyoxalase I) (Glx I) (Ketone-aldehyde mutase)(S-D-lactoylglutathione methylglyoxal lyase); (2977:) laeverin [Homosapiens]; (2978:) lambda-crystallin [Homo sapiens]; (2979:)Lambda-crystallin homolog; (2980:) Lamin-B receptor (Integral nuclearenvelope inner membrane protein) (LMN2R); (2981:) laminin alpha 3subunit isoform 1 [Homo sapiens]; (2982:) laminin alpha 3 subunitisoform 2 [Homo sapiens]; (2983:) laminin subunit beta 3 precursor [Homosapiens]; (2984:) laminin, gamma 2 isoform a precursor [Homo sapiens];(2985:) laminin, gamma 2 isoform b precursor [Homo sapiens]; (2986:)LANCL2 protein [Homo sapiens]; (2987:) lanthionine synthetase C-likeprotein 1 [Homo sapiens]; (2988:) Lariat debranching enzyme; (2989:)Latrophilin-1 precursor (Calcium-independent alpha-latrotoxinreceptor 1) (Lectomedin-2); (2990:) Latrophilin-2 precursor(Calcium-independent alpha-latrotoxin receptor 2) (Latrophilinhomolog 1) (Lectomedin-1); (2991:) Latrophilin-3 precursor(Calcium-independent alpha-latrotoxin receptor 3) (Lectomedin-3);(2992:) LBP-32 [Homo sapiens]; (2993:) LBP-9 [Homo sapiens]; (2994:)LCFA CoA ligase [Homo sapiens]; (2995:) leader-binding protein 32isoform 1 [Homo sapiens]; (2996:) leader-binding protein 32 isoform 2[Homo sapiens]; (2997:) Lecithin retinol acyltransferase(Phosphatidylcholine—retinolO-acyltransferase); (2998:) lecithin retinolacyltransferase [Homo sapiens]; (2999:) lecithin-cholesterolacyltransferase precursor [Homo sapiens]; (3000:) legumain preproprotein[Homo sapiens]; (3001:) legumaturain [Homo sapiens]; (3002:)leprecan-like 1 [Homo sapiens]; (3003:) leprecan-like 2 [Homo sapiens];(3004:) Leptin receptor precursor (LEP-R) (OB receptor) (OB-R) (HuB219)(CD295 antigen); (3005:) leucine aminopeptidase 3 [Homo sapiens];(3006:) leucine proline-enriched proteoglycan (leprecan) 1 [Homosapiens]; (3007:) leucine-rich alpha-2-glycoprotein 1 [Homo sapiens];(3008:) Leucine-rich repeat serine/threonine-protein kinase 1; (3009:)Leucine-rich repeat-containing G-protein coupled receptor 4precursor(G-protein coupled receptor 48); (3010:) Leucine-rich repeat-containingG-protein coupled receptor 5precursor (Orphan G-protein coupled receptorHG38) (G-protein coupled receptor 49) (G-protein coupled receptor 67);(3011:) Leucine-rich repeat-containing G-protein coupled receptor6(VTS20631); (3012:) leucyl aminopeptidase (EC 3.4.11.1)/prolylaminopeptidase (EC3.4.11.5)—human (fragment); (3013:) Leucyl-cystinylaminopeptidase (Cystinyl aminopeptidase) (Oxytocinase) (OTase)(Insulin-regulated membrane aminopeptidase) (Insulin-responsiveaminopeptidase) (IRAP) (Placental leucineaminopeptidase) (P-LAP);(3014:) Leukemia inhibitory factor receptor precursor (LIF receptor)(LIF-R) (CD118 antigen); (3015:) Leukocyte elastase precursor(Elastase-2) (Neutrophil elastase) (PMN elastase) (Bone marrow serineprotease) (Medullasin) (Human leukocyte elastase) (HLE); (3016:)Leukocyte immunoglobulin-like receptor subfamily A member 1 precursor(Leukocyte immunoglobulin-like receptor 6) (LIR-6) (CD85i antigen);(3017:) Leukocyte immunoglobulin-like receptor subfamily A member2precursor (Leukocyte immunoglobulin-like receptor 7) (LIR-7)(Immunoglobulin-like transcript 1) (ILT-1) (CD85h antigen); (3018:)Leukocyte immunoglobulin-like receptor subfamily A member 3precursor(Leukocyte immunoglobulin-like receptor 4) (LIR-4) (Immunoglobulin-liketranscript 6) (ILT-6) (Monocyte inhibitory receptor HM43/HM31) (CD85eantigen); (3019:) Leukocyte immunoglobulin-like receptor subfamily Amember 4precursor (Immunoglobulin-like transcript 7) (ILT-7) (CD85gantigen); (3020:) Leukocyte immunoglobulin-like receptor subfamily Bmember 1 precursor (Leukocyte immunoglobulin-like receptor 1) (LIR-1)(Immunoglobulin-like transcript 2) (ILT-2) (Monocyte/macrophageimmunoglobulin-like receptor 7) (MIR-7) (CD85j antigen); (3021:)Leukocyte immunoglobulin-like receptor subfamily B member 2precursor(Leukocyte immunoglobulin-like receptor 2) (LIR-2) (Immunoglobulin-liketranscript 4) (ILT-4) (Monocyte/macrophage immunoglobulin-like receptor10) (MIR-10) (CD85d antigen); (3022:) Leukocyte immunoglobulin-likereceptor subfamily B member 3precursor (Leukocyte immunoglobulin-likereceptor 3) (LIR-3) (Immunoglobulin-like transcript 5) (ILT-5) (Monocyteinhibitory receptor HL9) (CD85a antigen); (3023:) Leukocyteimmunoglobulin-like receptor subfamily B member 4precursor (Leukocyteimmunoglobulin-like receptor 5) (LIR-5) (Immunoglobulin-like transcript3) (ILT-3) (Monocyte inhibitory receptor HM18) (CD85k antigen); (3024:)Leukocyte immunoglobulin-like receptor subfamily B member 5precursor(Leukocyte immunoglobulin-like receptor 8) (LIR-8) (CD85c antigen);(3025:) Leukocyte tyrosine kinase receptor precursor (Protein tyrosinekinase 1); (3026:) Leukocyte-associated immunoglobulin-like receptor 1precursor (LAIR-1) (hLAIR1) (CD305 antigen); (3027:)Leukocyte-associated immunoglobulin-like receptor 2 precursor (LAIR-2)(CD306 antigen); (3028:) Leukotriene A-4 hydrolase (LTA-4 hydrolase)(Leukotriene A(4)hydrolase); (3029:) leukotriene A4 hydrolase [Homosapiens]; (3030:) leukotriene A-4 hydrolase precursor; (3031:)Leukotriene A4 hydrolase, LTA4 hydrolase [human, B-lymphocytic cell lineRaji, Peptide Partial, 21 aa]; (3032:) leukotriene A4 hydrolase; (3033:)leukotriene B4 receptor [Homo sapiens]; (3034:) Leukotriene B4 receptor1 (LTB4-R1) (P2Y purinoceptor 7) (P2Y7) (Chemoattractantreceptor-like 1) (G-protein coupled receptor 16); (3035:) Leukotriene B4receptor 2 (LTB4-R2) (Seven transmembrane receptor BLTR2) (LeukotrieneB4 receptor BLT2) (LTB4 receptor JULF2); (3036:) leukotriene C4 synthase(EC 6.-.-.-)—human; (3037:) leukotriene C4 synthase [Homo sapiens];(3038:) Lice2 alpha [Homo sapiens]; (3039:) Lice2 beta cysteine protease[Homo sapiens]; (3040:) Lice2 gamma cysteine protease [Homo sapiens];(3041:) ligase III, DNA, ATP-dependent isoform alpha precursor [Homosapiens]; (3042:) ligase III, DNA, ATP-dependent isoform beta precursor[Homo sapiens]; (3043:) Limb region 1 protein homolog(Differentiation-related gene 14protein); (3044:) lipase A precursor[Homo sapiens]; (3045:) lipase C precursor [Homo sapiens]; (3046:)Lipase member I precursor (Membrane-associated phosphatidicacid-selective phospholipase A1-beta) (mPA-PLA1 beta) (LPD lipase);(3047:) lipase, gastric [Homo sapiens]; (3048:) Lipid phosphatephosphohydrolase 1 (Phosphatidic acid phosphatase 2a) (Phosphatidatephosphohydrolase type 2a) (PAP2a) (PAP-2a) (PAP2-alpha); (3049:) Lipidphosphate phosphohydrolase 2 (Phosphatidic acid phosphatase 2c)(Phosphatidate phosphohydrolase type 2c) (PAP2c) (PAP-2c) (PAP2-gamma)(PAP2-G); (3050:) Lipid phosphate phosphohydrolase 3 (Phosphatidic acidphosphatase 2b) (Phosphatidate phosphohydrolase type 2b) (PAP2b)(PAP-2b) (PAP2-beta) (Vascular endothelial growth factor and type Icollagen-inducible protein) (VCIP); (3051:) lipin 1 [Homo sapiens];(3052:) Lipoamide acyltransferase component of branched-chainalpha-ketoacid dehydrogenase complex, mitochondrial precursor(Dihydrolipoyllysine-residue (2-methylpropanoyl)transferase) (E2)(Dihydrolipoamide branched chain transacylase) (BCKAD E2 subunit);(3053:) lipocalin 2 [Homo sapiens]; (3054:) Lipolysis-stimulatedlipoprotein receptor; (3055:) Lipoprotein lipase precursor (LPL);(3056:) lipoprotein lipase precursor [Homo sapiens]; (3057:) lipoproteinLp(a) precursor [Homo sapiens]; (3058:) lipoyl-containing component X[Homo sapiens]; (3059:) lipoyltransferase [Homo sapiens]; (3060:)lipoyltransferase 1 [Homo sapiens]; (3061:) Lipoyltransferase 1,mitochondrial precursor (Lipoate-protein ligase) (Lipoate biosynthesisprotein) (Lipoyl ligase); (3062:) Liver carboxylesterase 1 precursor(Acyl coenzyme A:cholesterolacyltransferase) (ACAT) (Monocyte/macrophageserine esterase) (HMSE) (Serine esterase 1) (Brain carboxylesterasehBr1) (Triacylglycerol hydrolase) (TGH) (Egasyn); (3063:) liverphosphofructokinase isoform a [Homo sapiens]; (3064:) liverphosphofructokinase isoform a variant [Homo sapiens]; (3065:) liverphosphofructokinase isoform b [Homo sapiens]; (3066:) liver-type1-phosphofructokinase [Homo sapiens]; (3067:) long chain fatty acyl CoAsynthetase 2 [Homo sapiens]; (3068:) long chain polyunsaturated fattyacid elongation enzyme [Homo sapiens]; (3069:) long-chain acyl-CoAsynthetase [Homo sapiens]; (3070:) long-chain acyl-CoA synthetase 5[Homo sapiens]; (3071:) long-chain acyl-CoA synthetase; (3072:)Long-chain fatty acid transport protein 1 (Fatty acid transportprotein 1) (FATP-1) (Solute carrier family 27 member 1); (3073:)Long-chain fatty acid transport protein 3 (Fatty acid transport protein3) (FATP-3) (Very long-chain acyl-CoA synthetase homolog 3) (VLCS-3)(Solute carrier family 27 member 3); (3074:) Long-chain fatty acidtransport protein 4 (Fatty acid transport protein 4) (FATP-4) (Solutecarrier family 27 member 4); (3075:) Long-chain fatty acid transportprotein 6 (Fatty acid transport protein 6) (FATP-6) (Very long-chainacyl-CoA synthetase homolog 1) (VLCSH1) (hVLCS-H1) (Fatty-acid-coenzymeA ligase, very long-chain 2) (Solute carrier family 27 member 6);(3076:) Long-chain-fatty-acid—CoA ligase 1 (Long-chain acyl-CoAsynthetase 1) (LACS1) (Palmitoyl-CoA ligase 1) (Long-chain fatty acidCoA ligase 2) (Long-chain acyl-CoA synthetase 2) (LACS 2) (Acyl-CoAsynthetase 1) (ACS1) (Palmitoyl-CoA ligase 2); (3077:)Long-chain-fatty-acid—CoA ligase 3 (Long-chain acyl-CoA synthetase 3)(LACS 3); (3078:) Long-chain-fatty-acid—CoA ligase 4 (Long-chainacyl-CoA synthetase 4) (LACS 4); (3079:) Long-chain-fatty-acid—CoAligase 5 (Long-chain acyl-CoA synthetase 5) (LACS 5); (3080:)Long-chain-fatty-acid—CoA ligase 6 (Long-chain acyl-CoA synthetase 6)(LACS 6); (3081:) “Low affinity immunoglobulin epsilon Fc receptor(Lymphocyte IgE receptor) (Fc-epsilon-RII) (BLAST-2) (ImmunoglobulinE-binding factor) (CD23 antigen) [Contains:) Low affinity immunoglobulinepsilon Fc receptor membrane-bound form; Low affinity immunoglobulinepsilon Fc receptor soluble form].”; (3082:) Low affinity immunoglobulingamma Fc region receptor II-a precursor (Fc-gamma RII-a) (FcRII-a) (IgGFc receptor II-a) (Fc-gamma-RIIa) (CD32 antigen) (CDw32); (3083:) Lowaffinity immunoglobulin gamma Fc region receptor II-b precursor(Fc-gamma RII-b) (FcRII-b) (IgG Fc receptor II-b) (Fc-gamma-RIIb) (CD32antigen) (CDw32); (3084:) Low affinity immunoglobulin gamma Fc regionreceptor II-c precursor (Fc-gamma RII-c) (FcRII-c) (IgG Fc receptorII-c) (Fc-gamma-RIIc) (CD32 antigen) (CDw32); (3085:) Low affinityimmunoglobulin gamma Fc region receptor III-A precursor (IgG Fc receptorIII-2) (Fc-gamma RIII-alpha) (Fc-gamma RIIIa) (FcRIIIa) (Fc-gamma RIII)(FcRIII) (FcR-10) (CD16a antigen); (3086:) Low affinity immunoglobulingamma Fc region receptor III-B precursor (IgG Fc receptor III-1)(Fc-gamma RIII-beta) (Fc-gamma RIIIb) (FcRIIIb) (Fc-gamma RIII) (FcRIII)(FcR-10) (CD16b antigen); (3087:) low density lipoprotein receptorprecursor [Homo sapiens]; (3088:) low density lipoprotein-relatedprotein 1 [Homo sapiens]; (3089:) Low molecular weight phosphotyrosineprotein phosphatase (LMW-PTP) (Low molecular weight cytosolic acidphosphatase) (Red cell acid phosphatase 1) (PTPase) (Adipocyte acidphosphatase); (3090:) Low-density lipoprotein receptor precursor (LDLreceptor); (3091:) Low-density lipoprotein receptor-related protein 1precursor (LRP) (Alpha-2-macroglobulin receptor) (A2MR) (ApolipoproteinE receptor) (APOER) (CD91 antigen); (3092:) Low-density lipoproteinreceptor-related protein 10 precursor; (3093:) Low-density lipoproteinreceptor-related protein 11 precursor; (3094:) Low-density lipoproteinreceptor-related protein 12 precursor (Suppressor of tumorigenicityprotein 7); (3095:) Low-density lipoprotein receptor-related protein 1Bprecursor (Low-density lipoprotein receptor-related protein-deleted intumor) (LRP-DIT); (3096:) Low-density lipoprotein receptor-relatedprotein 2 precursor (Megalin) (Glycoprotein 330) (gp330); (3097:)Low-density lipoprotein receptor-related protein 3 precursor (hLRp105);(3098:) Low-density lipoprotein receptor-related protein 4 precursor(Multiple epidermal growth factor-like domains 7); (3099:) Low-densitylipoprotein receptor-related protein 5 precursor; (3100:) Low-densitylipoprotein receptor-related protein 6 precursor; (3101:) Low-densitylipoprotein receptor-related protein 8 precursor (Apolipoprotein Ereceptor 2); (3102:) L-pipecolic acid oxidase [Homo sapiens]; (3103:)LRAP protein [Homo sapiens]; (3104:) L-serine dehydratase (L-serinedeaminase); (3105:) L-UBC [Homo sapiens]; (3106:) luteinizinghormone/choriogonadotropin receptor precursor [Homo sapiens]; (3107:)Lutheran blood group glycoprotein precursor (B-CAM cell surfaceglycoprotein) (Auberger B antigen) (F8/G253 antigen) (CD239antigen);(3108:) Lutropin-choriogonadotropic hormone receptor precursor (LH/CG-R)(LSH-R) (Luteinizing hormone receptor) (LHR); (3109:) L-xylulosereductase (XR) (Dicarbonyl/L-xylulose reductase) (Kidney dicarbonylreductase) (kiDCR) (Carbonyl reductase II) (Sperm surface protein P34H);(3110:) Lymphatic vessel endothelial hyaluronic acid receptor 1precursor (LYVE-1) (Cell surface retention sequence-binding protein 1)(CRSBP-1) (Hyaluronic acid receptor) (Extracellular linkdomain-containing protein 1); (3111:) Lymphocyte antigen 75 precursor(DEC-205) (gp200-MR6) (CD205antigen); (3112:) Lysine-specific histonedemethylase 1 (Flavin-containing amineoxidase domain-containing protein2) (BRAF35-HDAC complex protein BHC110); (3113:) Lysophosphatidic acidreceptor 4 (LPA receptor 4) (LPA-4) (P2Y purinoceptor 9) (P2Y9)(Purinergic receptor 9) (G-protein coupled receptor 23) (P2Y5-likereceptor); (3114:) Lysophosphatidic acid receptor Edg-2 (LPA receptor 1)(LPA-1); (3115:) Lysophosphatidic acid receptor Edg-4 (LPA receptor 2)(LPA-2); (3116:) Lysophosphatidic acid receptor Edg-7 (LPA receptor 3)(LPA-3); (3117:) lysophospholipase 3 (lysosomal phospholipase A2) [Homosapiens]; (3118:) “Lysosomal alpha-glucosidase precursor (Acid maltase)(Aglucosidasealfa) [Contains:) 76 kDa lysosomal alpha-glucosidase; 70kDa lysosomal alpha-glucosidase].”; (3119:) “Lysosomal alpha-mannosidaseprecursor (Mannosidase, alpha B) (Lysosomal acid alpha-mannosidase)(Laman) (Mannosidase alpha class 2B member 1) [Contains:) Lysosomalalpha-mannosidase A peptide; Lysosomal alpha-mannosidase B peptide;Lysosomal alpha-mannosidase C peptide; Lysosomal alpha-mannosidase Dpeptide; Lysosomal alpha-mannosidase E peptide].”; (3120:) lysosomalenzyme beta-N-acetylhexosaminidase A [Homo sapiens]; (3121:) lysosomalglucocerebrosidase precursor [Homo sapiens]; (3122:) lysosomalneuraminidase precursor [Homo sapiens]; (3123:) “Lysosomal protectiveprotein precursor (Cathepsin A) (Carboxypeptidase C) (Protective proteinfor beta-galactosidase)[Contains:) Lysosomal protective protein 32 kDachain; Lysosomal protective protein 20 kDa chain].”; (3124:) Lysosomalthioesterase PPT2 precursor (PPT-2) (S-thioesterase G14); (3125:)Lysosome membrane protein 2 (Lysosome membrane protein II) (LIMPII)(Scavenger receptor class B member 2) (85 kDa lysosomal membrane sialoglycoprotein) (LGP85) (CD36 antigen-like 2); (3126:) Lysozyme-likeprotein 4 precursor; (3127:) lysyl hydroxylase precursor [Homo sapiens];(3128:) lysyl oxidase preproprotein [Homo sapiens]; (3129:) lysyloxidase-like 2 precursor [Homo sapiens]; (3130:) lysyl oxidase-like 3precursor [Homo sapiens]; (3131:) lysyl-tRNA synthetase [Homo sapiens];(3132:) M2-type pyruvate kinase; (3133:) MACH-alpha-1 [Homo sapiens];(3134:) MACH-alpha-2 [Homo sapiens]; (3135:) MACH-alpha-3 [Homosapiens]; (3136:) MACH-beta-3 [Homo sapiens]; (3137:) MACH-beta-4 [Homosapiens]; (3138:) Macrophage colony-stimulating factor 1 receptorprecursor (CSF-1-R) (Fms proto-oncogene) (c-fms) (CD115 antigen);(3139:) Macrophage mannose receptor 1 precursor (MMR) (CD206 antigen);(3140:) Macrophage mannose receptor 2 precursor (Urokinasereceptor-associated protein) (Endocytic receptor 180) (CD280antigen);(3141:) Macrophage receptor MARCO (Macrophage receptor with collagenousstructure) (Scavenger receptor class A member 2); (3142:) Macrophagescavenger receptor types I and II (Macrophage acetylated LDL receptor Iand II) (Scavenger receptor class A member 1) (CD204antigen); (3143:)“Macrophage-stimulating protein receptor precursor (MSP receptor)(p185-Ron) (CD136 antigen) (CDw136) [Contains: Macrophage-stimulatingprotein receptor alpha chain; Macrophage-stimulating protein receptorbeta chain].”; (3144:) Magnesium-dependent phosphatase 1 (MDP-1);(3145:) major histocompatibility complex, class II, DP alpha 1precursor[Homo sapiens]; (3146:) major histocompatibility complex, classII, DQ alpha 2 [Homo sapiens]; (3147:) malate dehydrogenase(oxaloacetate decarboxylating) (NADP+) [Homo sapiens]; (3148:) malesterility domain containing 1 [Homo sapiens]; (3149:) male sterilitydomain containing 2 [Homo sapiens]; (3150:) Maleylacetoacetate isomerase(MAAI) (Glutathione S-transferase zeta1) (GSTZ1-1); (3151:) Malic enzyme1, NADP(+)-dependent, cytosolic [Homo sapiens]; (3152:) malic enzyme 2[Homo sapiens]; (3153:) malic enzyme 2, NAD(+)-dependent, mitochondrial[Homo sapiens]; (3154:) malic enzyme 3, NADP(+)-dependent, mitochondrial[Homo sapiens]; (3155:) Malonyl CoA-acyl carrier protein transacylase,mitochondrial precursor (MCT) (Mitochondrial malonyltransferase);(3156:) maltase-glucoamylase [Homo sapiens]; (3157:) manganesesuperoxide dismutase isoform A precursor [Homo sapiens]; (3158:)manganese superoxide dismutase isoform B precursor [Homo sapiens];(3159:) mannan-binding lectin serine protease 2 isoform 1 precursor[Homo sapiens]; (3160:) mannan-binding lectin serine protease 2 isoform2 precursor [Homo sapiens]; (3161:) “Mannan-binding lectin serineprotease 2 precursor (Mannose-binding protein-associated serine protease2) (MASP-2) (MBL-associated serine protease 2) [Contains:)Mannan-binding lectin serine protease 2 A chain; Mannan-binding lectinserine protease 2 B chain].”; (3162:) mannosidase, alpha, class 1A,member 1 [Homo sapiens]; (3163:) mannosidase, alpha, class 2A, member 1[Homo sapiens]; (3164:) mannosidase, alpha, class 2B, member 1 precursor[Homo sapiens]; (3165:) mannosidase, alpha, class 2C, member 1 [Homosapiens]; (3166:) mannosidase, endo-alpha [Homo sapiens]; (3167:)mannosyl (alpha-1,3-)-glycoproteinbeta-1,2-N-acetylglucosaminyltransferase [Homo sapiens]; (3168:)mannosyl (alpha-1,6-)-glycoproteinbeta-1,2-N-acetylglucosaminyltransferase [Homo sapiens]; (3169:)mannosyl (beta-1,4-)-glycoproteinbeta-1,4-N-acetylglucosaminyltransferase [Homo sapiens]; (3170:)Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (Processingalpha-1,2-mannosidase IA) (Alpha-1,2-mannosidase IA) (Mannosidase alphaclass IA member 1) (Man(9)-alpha-mannosidase) (Man9-mannosidase);(3171:) Mannosyl-oligosaccharide 1,2-alpha-mannosidase IB (Processingalpha-1,2-mannosidase IB) (Alpha-1,2-mannosidase IB) (Mannosidase alphaclass 1A member 2); (3172:) Mannosyl-oligosaccharide1,2-alpha-mannosidase IC (Processing alpha-1,2-mannosidase IC)(Alpha-1,2-mannosidase IC) (Mannosidase alpha class IC member 1) (HMIC);(3173:) mannosyl-oligosaccharide glucosidase [Homo sapiens]; (3174:) MAPkinase-activated protein kinase 2 (MAPK-activated protein kinase 2)(MAPKAP kinase 2) (MAPKAPK-2) (MK2); (3175:) MAP kinase-activatedprotein kinase 5 (MAPK-activated protein kinase 5) (MAPKAP kinase 5)(p38-regulated/activated protein kinase); (3176:) MAP kinase-interactingserine/threonine-protein kinase 1 (MAP kinase signal-integratingkinase 1) (Mnk1); (3177:) MAPK/MAK/MRK overlapping kinase (MOK proteinkinase) (Renal tumor antigen 1) (RAGE-1); (3178:) marapsin [Homosapiens]; (3179:) MAS proto-oncogene; (3180:) masA [Homo sapiens];(3181:) Mas-related G-protein coupled receptor member D (Beta-alaninereceptor) (G-protein coupled receptor TGR7); (3182:) Mas-relatedG-protein coupled receptor member E (G-protein coupled receptor 167);(3183:) Mas-related G-protein coupled receptor member F (Mas-relatedgene F protein) (G-protein coupled receptor 168); (3184:) Mas-relatedG-protein coupled receptor member G (G-protein coupled receptor 169);(3185:) Mas-related G-protein coupled receptor member XI (Sensoryneuron-specific G-protein coupled receptor 3/4); (3186:) Mas-relatedG-protein coupled receptor member X2; (3187:) Mas-related G-proteincoupled receptor member X3 (Sensory neuron-specific G-protein coupledreceptor 1/2); (3188:) Mas-related G-protein coupled receptor member X4(Sensory neuron-specific G-protein coupled receptor 5/6); (3189:)Mas-related G-protein coupled receptor MRG (MAS-R) (MAS1-like); (3190:)mast cell function-associated antigen [Homo sapiens]; (3191:) Mast/stemcell growth factor receptor precursor (SCFR) (Proto-oncogenetyrosine-protein kinase Kit) (c-kit) (CD117antigen); (3192:) matrixmetalloproteinase 1 preproprotein [Homo sapiens]; (3193:) matrixmetalloproteinase 10 preproprotein [Homo sapiens]; (3194:) matrixmetalloproteinase 11 preproprotein [Homo sapiens]; (3195:) matrixmetalloproteinase 12 preproprotein [Homo sapiens]; (3196:) matrixmetalloproteinase 13 preproprotein [Homo sapiens]; (3197:) matrixmetalloproteinase 14 preproprotein [Homo sapiens]; (3198:) matrixmetalloproteinase 15 preproprotein [Homo sapiens]; (3199:) matrixmetalloproteinase 16 isoform 1 preproprotein [Homo sapiens]; (3200:)matrix metalloproteinase 16 isoform 2 preproprotein [Homo sapiens];(3201:) matrix metalloproteinase 17 preproprotein [Homo sapiens];(3202:) matrix metalloproteinase 19 isoform 2 precursor [Homo sapiens];(3203:) matrix metalloproteinase 19 isoform rasi-1 preproprotein [Homosapiens]; (3204:) matrix metalloproteinase 2 preproprotein [Homosapiens]; (3205:) matrix metalloproteinase 20 preproprotein [Homosapiens]; (3206:) matrix metalloproteinase 23B precursor [Homo sapiens];(3207:) matrix metalloproteinase 26 preproprotein [Homo sapiens];(3208:) matrix metalloproteinase 28 isoform 1 preproprotein [Homosapiens]; (3209:) matrix metalloproteinase 28 isoform 3 [Homo sapiens];(3210:) matrix metalloproteinase 3 preproprotein [Homo sapiens]; (3211:)matrix metalloproteinase 7 preproprotein [Homo sapiens]; (3212:) matrixmetalloproteinase 8 preproprotein [Homo sapiens]; (3213:) matrixmetalloproteinase 9 preproprotein [Homo sapiens]; (3214:) Matrixmetalloproteinase-16 precursor (MMP-16) (Membrane-type matrixmetalloproteinase 3) (MT-MMP 3) (MTMMP3) (Membrane-type-3matrixmetalloproteinase) (MT3-MMP) (MT3MMP) (MMP-X2); (3215:) Matrixmetalloproteinase-19 precursor (MMP-19) (Matrixmetalloproteinase RASI)(MMP-18); (3216:) “Matrix metalloproteinase-9 precursor (MMP-9) (92 kDatype IV collagenase) (92 kDa gelatinase) (Gelatinase B) (GELB)[Contains:67 kDa matrix metalloproteinase-9; 82 kDa matrixmetalloproteinase-9].”; (3217:) matrix, extracellularphosphoglycoprotein with ASARM motif (bone)[Homo sapiens]; (3218:) Mch3isoform alpha; (3219:) Mch3 isoform beta; (3220:) “MDMCSF (EC 1.5.1.5;EC 3.5.4.9; EC 6.3.4.3).”; (3221:) MDS010 [Homo sapiens]; (3222:) ME2protein [Homo sapiens]; (3223:) Mediator complex subunit 4 (Mediator ofRNA polymerase II transcription subunit 4) (Vitamin D3receptor-interacting protein complex 36 kDa component) (DRIP36)(Activator-recruited cofactor 36 kDa component) (ARC36) (TRAP/SMCC/PC2subunit p36 subunit); (3224:) Mediator of RNA polymerase IItranscription subunit 12 (Thyroid hormone receptor-associated proteincomplex 230 kDa component) (Trap230) (Activator-recruited cofactor 240kDa component) (ARC240) (CAG repeat protein 45) (OPA-containing protein)(Trinucleotide repeat-containing gene 11 protein); (3225:) Mediator ofRNA polymerase II transcription subunit 8 homolog (Activator-recruitedcofactor 32 kDa component) (ARC32); (3226:) mediator of RNA polymeraseII transcription subunit MED8 isoform 1 [Homo sapiens]; (3227:) mediatorof RNA polymerase II transcription subunit MED8 isoform 2 [Homosapiens]; (3228:) mediator of RNA polymerase II transcription subunitMED8 isoform 3 [Homo sapiens]; (3229:) mediator of RNA polymerase IItranscription subunit MED8 isoform 4 [Homo sapiens]; (3230:)medium-chain acyl-CoA dehydrogenase (EC 1.3.99.3); (3231:) medium-chainacyl-CoA dehydrogenase; (3232:) Medium-chain specific acyl-CoAdehydrogenase, mitochondrial precursor (MCAD); (3233:) Meis1 homolog[Homo sapiens]; (3234:) Melanin-concentrating hormone receptor 1 (MCHreceptor 1) (MCHR-1) (MCH-R1) (MCHIR) (MCH-1R) (MCHR) (G-protein coupledreceptor 24) (Somatostatin receptor-like protein) (SLC-1); (3235:)Melanin-concentrating hormone receptor 2 (MCH receptor 2) (MCHR-2)(MCH-R2) (MCH2R) (MCH-2R) (MCH2) (G-protein coupled receptor 145)(GPRv17); (3236:) Melanocortin receptor 3 (MC3-R); (3237:) Melanocortinreceptor 4 (MC4-R); (3238:) Melanocortin receptor 5 (MC5-R) (MC-2);(3239:) Melanocyte protein PmeI 17 precursor (Melanocytelineage-specific antigen GP100) (Melanoma-associated ME20 antigen)(ME20M/ME20S) (ME20-M/ME20-S) (95 kDa melanocyte-specific secretedglycoprotein); (3240:) Melanocyte-stimulating hormone receptor (MSH-R)(Melanotropin receptor) (Melanocortin receptor 1) (MC1-R); (3241:)Melanopsin (Opsin-4); (3242:) Melatonin receptor type 1A (MeI-1A-R)(MeI1a melatonin receptor); (3243:) Melatonin receptor type 1B(MeI-1B-R) (MeI1b melatonin receptor); (3244:) Melatonin-relatedreceptor (G protein-coupled receptor 50) (H9); (3245:) membrane alanineaminopeptidase precursor [Homo sapiens]; (3246:) membrane associatedguanylate kinase, WW and PDZ domain containing 2 [Homo sapiens]; (3247:)Membrane copper amine oxidase (Semicarbazide-sensitive amineoxidase)(SSAO) (Vascular adhesion protein 1) (VAP-1) (HPAO); (3248:) membranemetallo-endopeptidase [Homo sapiens]; (3249:) Membranemetallo-endopeptidase-like 1 (Membrane metallo-endopeptidase-like 2)(Neprilysin-2) (Neprilysin II) (NL2) (NEPII) (NEP2(m)) [Contains:)Membrane metallo-endopeptidase-like 1, soluble form (Neprilysin-2secreted) (NEP2(s))]; (3250:) Membrane progestin receptor alpha (mPRalpha) (Progestin and adipoQ receptor family member VII); (3251:)Membrane progestin receptor beta (mPR beta) (Progestin and adipoQreceptor family member VI II) (Lysosomal membrane protein in brain-1);(3252:) Membrane progestin receptor gamma (mPR gamma) (Progestin andadipoQ receptor family member V); (3253:) Membrane-associatedprogesterone receptor component 1 (mPR); (3254:) Membrane-associatedprogesterone receptor component 2 (Progesterone membrane-bindingprotein) (Steroid receptor protein DG6); (3255:) membrane-associatedprostaglandin E synthase (EC 5.3.99.3)-2-human; (3256:)Membrane-associated tyrosine- and threonine-specific cdc2-inhibitorykinase (Myt1 kinase); (3257:) Membrane-bound transcription factor site 1protease precursor (S1 Pendopeptidase) (Site-1 protease)(Subtilisin/kexin-isozyme 1) (SKI-1); (3258:) Membrane-spanning4-domains subfamily A member 10; (3259:) Membrane-spanning 4-domainssubfamily A member 12; (3260:) Membrane-spanning 4-domains subfamily Amember 3(Hematopoietic-specific transmembrane 4 protein) (HTm4) (CD20antigen-like protein); (3261:) Membrane-spanning 4-domains subfamily Amember 4A (Four-span transmembrane protein 1) (CD20 antigen-like 1);(3262:) Membrane-spanning 4-domains subfamily A member 4E; (3263:)Membrane-spanning 4-domains subfamily A member 5 (Testis-expressedtransmembrane 4 protein) (CD20 antigen-like 2); (3264:)Membrane-spanning 4-domains subfamily A member 6A (Four-spantransmembrane protein 3) (CD20 antigen-like 3); (3265:)Membrane-spanning 4-domains subfamily A member 6E; (3266:)Membrane-spanning 4-domains subfamily A member 7(CD20/FC-epsilon-RI-betafamily member 4) (Four-span transmembrane protein 2) (CD20 antigen-like4); (3267:) Membrane-spanning 4-domains subfamily A member 8B (Four-spantransmembrane protein 4); (3268:) membrane-type mosaic serine protease[Homo sapiens]; (3269:) menage a trois 1 (CAK assembly factor) [Homosapiens]; (3270:) meningioma expressed antigen 5 (hyaluronidase) [Homosapiens]; (3271:) meprin A, alpha (PABA peptide hydrolase) [Homosapiens]; (3272:) meprin A, beta [Homo sapiens]; (3273:)mercaptopyruvate sulfur transferase variant [Homo sapiens]; (3274:)mesotrypsin preproprotein [Homo sapiens]; (3275:) mesotrypsinogen [Homosapiens]; (3276:) Metabotropic glutamate receptor 1 precursor (mGluR1);(3277:) Metabotropic glutamate receptor 2 precursor (mGluR2); (3278:)Metabotropic glutamate receptor 3 precursor (mGluR3); (3279:)Metabotropic glutamate receptor 4 precursor (mGluR4); (3280:)metabotropic glutamate receptor 5 A—human; (3281:) metabotropicglutamate receptor 5 B—human; (3282:) Metabotropic glutamate receptor 5precursor (mGluR5); (3283:) Metabotropic glutamate receptor 6 precursor(mGluR6); (3284:) Metabotropic glutamate receptor 7 precursor (mGluR7);(3285:) Metabotropic glutamate receptor 8 precursor (mGluR8); (3286:)metallopeptidase [Homo sapiens]; (3287:) metallothionein 1A [Homosapiens]; (3288:) methionine sulfoxide reductase A [Homo sapiens];(3289:) methionine synthase reductase isoform 1 [Homo sapiens]; (3290:)methionine synthase reductase isoform 2 [Homo sapiens]; (3291:)methionyl aminopeptidase 2 [Homo sapiens]; (3292:) Methionyl-tRNAsynthetase, mitochondrial precursor (Methionine—tRNA ligase 2)(Mitochondrial methionine—tRNA ligase) (MtMetRS); (3293:) methyl steroloxidase; (3294:) Methylated-DNA—protein-cysteine methyltransferase(6-O-methylguanine-DNA methyltransferase) (MGMT)(O-6-methylguanine-DNA-alkyltransferase); (3295:) Methylcrotonoyl-CoAcarboxylase subunit alpha, mitochondrial precursor (3-methylcrotonyl-CoAcarboxylase 1) (MC Case subunit alpha) (3-methylcrotonyl-CoA:carbondioxide ligase subunit alpha) (3-methylcrotonyl-CoA carboxylasebiotin-containing subunit); (3296:) methylcrotonoyl-Coenzyme Acarboxylase 1 (alpha) [Homo sapiens]; (3297:) methylcrotonoyl-Coenzyme Acarboxylase 1 (alpha) variant [Homo sapiens]; (3298:)methylcrotonoyl-Coenzyme A carboxylase 2 (beta) [Homo sapiens]; (3299:)methylene tetrahydrofolate dehydrogenase 2 isoform A precursor[Homosapiens]; (3300:) methylene tetrahydrofolate dehydrogenase 2 isoform B[Homo sapiens]; (3301:) methylenetetrahydrofolate dehydrogenase (NADP+dependent) 1-like [Homo sapiens]; (3302:) methylenetetrahydrofolatedehydrogenase 1 [Homo sapiens]; (3303:) methylenetetrahydrofolatereductase [Homo sapiens]; (3304:) methylenetetrahydrofolate reductaseintermediate form [Homo sapiens]; (3305:) methylenetetrahydrofolatereductase long isoform [Homo sapiens]; (3306:) methylenetetrahydrofolatereductase short isoform [Homo sapiens]; (3307:)Methylenetetrahydrofolate reductase; (3308:) methylmalonyl Coenzyme Amutase precursor [Homo sapiens]; (3309:) Methylmalonyl-CoA mutase,mitochondrial precursor (MCM) (Methylmalonyl-CoA isomerase); (3310:)methylthioadenosine phosphorylase [Homo sapiens]; (3311:)methyltransferase like 3 [Homo sapiens]; (3312:) Mevalonate kinase (MK);(3313:) mevalonate kinase [Homo sapiens]; (3314:) mevalonatepyrophosphate decarboxylase; (3315:) MGC42638 protein [Homo sapiens];(3316:) microphthalmia-associated transcription factor isoform 1 [Homosapiens]; (3317:) microphthalmia-associated transcription factor isoform2 [Homo sapiens]; (3318:) microphthalmia-associated transcription factorisoform 3 [Homo sapiens]; (3319:) microphthalmia-associatedtranscription factor isoform 4 [Homo sapiens]; (3320:)microphthalmia-associated transcription factor isoform 5 [Homo sapiens];(3321:) microphthalmia-associated transcription factor isoform 6 [Homosapiens]; (3322:) Microsomal glutathione S-transferase 1 (MicrosomalGST-1) (Microsomal GST-1); (3323:) microsomal glutathione S-transferase2 [Homo sapiens]; (3324:) Microsomal glutathione S-transferase 3(Microsomal GST-3) (Microsomal GST-III); (3325:) microsomal glutathioneS-transferase 3 [Homo sapiens]; (3326:) microtubule-associated proteintau isoform 1 [Homo sapiens]; (3327:) microtubule-associated protein tauisoform 2 [Homo sapiens]; (3328:) microtubule-associated protein tauisoform 3 [Homo sapiens]; (3329:) microtubule-associated protein tauisoform 4 [Homo sapiens]; (3330:) microtubule-associated proteins 1A/1Blight chain 3 [Homo sapiens]; (3331:) migration-inducing gene 10 protein[Homo sapiens]; (3332:) migration-inducing protein 4 [Homo sapiens];(3333:) Mih1/TX isoform beta [Homo sapiens]; (3334:) Mih1/TX isoformdelta [Homo sapiens]; (3335:) Mih1/TX isoform gamma [Homo sapiens];(3336:) Mineralocorticoid receptor (MR); (3337:) minichromosomemaintenance protein 4 [Homo sapiens]; (3338:) minichromosome maintenanceprotein 6 [Homo sapiens]; (3339:) minichromosome maintenance protein 7isoform 1 [Homo sapiens]; (3340:) minichromosome maintenance protein 7isoform 2 [Homo sapiens]; (3341:) mitochondrial aldehyde dehydrogenase 2precursor [Homo sapiens]; (3342:) mitochondrial C1-tetrahydrofolatesynthetase—human; (3343:) mitochondrial dihydrolipoamidesuccinyltransferase [Homo sapiens]; (3344:) mitochondrial DNA polymeraseaccessory subunit precursor [Homo sapiens]; (3345:) mitochondrialglycine cleavage system H-protein precursor [Homo sapiens]; (3346:)Mitochondrial import receptor subunit TOM22 homolog (Translocase ofouter membrane 22 kDa subunit homolog) (hTom22) (1C9-2); (3347:)Mitochondrial intermediate peptidase, mitochondrial precursor (MIP);(3348:) mitochondrial malate dehydrogenase precursor [Homo sapiens];(3349:) mitochondrial MTO1-3 [Homo sapiens]; (3350:) mitochondrialNAD(P)+-dependent malic enzyme; (3351:) mitochondrial NADP(+)-dependentmalic enzyme 3 [Homo sapiens]; (3352:) mitochondrial phosphoenolpyruvatecarboxykinase 2 isoform 1 precursor [Homo sapiens]; (3353:)mitochondrial phosphoenolpyruvate carboxykinase 2 isoform 2precursor[Homo sapiens]; (3354:) mitochondrial short-chain enoyl-coenzyme Ahydratase 1 precursor[Homo sapiens]; (3355:) mitochondrial topoisomeraseI [Homo sapiens]; (3356:) Mitochondrial translation optimization 1homolog (S. cerevisiae)[Homo sapiens]; (3357:) mitochondrial translationoptimization 1 homolog isoform a [Homo sapiens]; (3358:) mitochondrialtranslation optimization 1 homolog isoform b [Homo sapiens]; (3359:)mitochondrial trifunctional protein, alpha subunit precursor [Homosapiens]; (3360:) mitochondrial trifunctional protein, beta subunitprecursor [Homo sapiens]; (3361:) Mitogen-activated protein kinase 1(Extracellular signal-regulated kinase 2) (ERK-2) (Mitogen-activatedprotein kinase 2) (MAP kinase 2) (MAPK 2) (p42-MAPK) (ERT1); (3362:)mitogen-activated protein kinase 1 [Homo sapiens]; (3363:)Mitogen-activated protein kinase 10 (Stress-activated protein kinaseJNK3) (c-Jun N-terminal kinase 3) (MAP kinase p49 3F12); (3364:)Mitogen-activated protein kinase II (Mitogen-activated protein kinasep38 beta) (MAP kinase p38 beta) (p38b) (p38-2) (Stress-activated proteinkinase 2); (3365:) Mitogen-activated protein kinase 12 (Extracellularsignal-regulated kinase 6) (ERK-6) (ERK5) (Stress-activated proteinkinase 3) (Mitogen-activated protein kinase p38 gamma) (MAP kinasep38gamma); (3366:) Mitogen-activated protein kinase 13 (Stress-activatedprotein kinase 4) (Mitogen-activated protein kinase p38 delta) (MAPkinase p38 delta); (3367:) Mitogen-activated protein kinase 14(Mitogen-activated protein kinase p38 alpha) (MAP kinase p38 alpha)(Cytokine suppressive anti-inflammatory drug-binding protein)(CSAID-binding protein) (CSBP) (MAX-interacting protein 2) (MAP kinaseMXI2) (SAPK2A); (3368:) Mitogen-activated protein kinase 15(Extracellular signal-regulated kinase 8); (3369:) Mitogen-activatedprotein kinase 3 (Extracellular signal-regulated kinase 1) (ERK-1)(Insulin-stimulated MAP2 kinase) (MAP kinase 1) (MAPK 1) (p44-ERK1)(ERT2) (p44-MAPK) (Microtubule-associated protein 2 kinase); (3370:)mitogen-activated protein kinase 3 isoform 1 [Homo sapiens]; (3371:)mitogen-activated protein kinase 3 isoform 2 [Homo sapiens]; (3372:)Mitogen-activated protein kinase 7 (Extracellular signal-regulatedkinase 5) (ERK-5) (ERK4) (BMK1 kinase); (3373:) Mitogen-activatedprotein kinase 8 (Stress-activated protein kinase JNK1) (c-JunN-terminal kinase 1) (JNK-46); (3374:) mitogen-activated protein kinase8 isoform JNK1 alpha1 [Homo sapiens]; (3375:) mitogen-activated proteinkinase 8 isoform JNK1 alpha2 [Homo sapiens]; (3376:) mitogen-activatedprotein kinase 8 isoform JNK1 beta1 [Homo sapiens]; (3377:)mitogen-activated protein kinase 8 isoform JNK1 beta2 [Homo sapiens];(3378:) Mitogen-activated protein kinase 9 (Stress-activated proteinkinase JNK2) (c-Jun N-terminal kinase 2) (JNK-55); (3379:)mitogen-activated protein kinase kinase 1 [Homo sapiens]; (3380:)Mitogen-activated protein kinase kinase kinase (Mixed lineage kinase 4);(3381:) Mitogen-activated protein kinase kinase kinase 1 (MAPK/ERKkinase kinase 1) (MEK kinase 1) (MEKK1); (3382:) Mitogen-activatedprotein kinase kinase kinase 10 (Mixed lineage kinase 2) (Protein kinaseMST); (3383:) Mitogen-activated protein kinase kinase kinase II (Mixedlineage kinase 3) (Src-homology 3 domain-containing proline-richkinase); (3384:) mitogen-activated protein kinase kinase kinase 12 [Homosapiens]; (3385:) Mitogen-activated protein kinase kinase kinase 13(Mixed lineage kinase) (MLK) (Leucine zipper-bearing kinase); (3386:)Mitogen-activated protein kinase kinase kinase 15 (MAPK/ERK kinasekinase 15) (MEK kinase 15) (MEKK 15); (3387:) Mitogen-activated proteinkinase kinase kinase 2 (MAPK/ERK kinase kinase 2) (MEK kinase 2) (MEKK2); (3388:) Mitogen-activated protein kinase kinase kinase 3 (MAPK/ERKkinase kinase 3) (MEK kinase 3) (MEKK 3); (3389:) Mitogen-activatedprotein kinase kinase kinase 4 (MAPK/ERK kinase kinase 4) (MEK kinase 4)(MEKK 4) (MAP three kinase 1); (3390:) Mitogen-activated protein kinasekinase kinase 5 (MAPK/ERK kinase kinase 5) (MEK kinase 5) (MEKK 5)(Apoptosis signal-regulating kinase 1) (ASK-1); (3391:)mitogen-activated protein kinase kinase kinase 5 [Homo sapiens]; (3392:)Mitogen-activated protein kinase kinase kinase 6; (3393:)Mitogen-activated protein kinase kinase kinase 9 (Mixed lineage kinase1); (3394:) Mitogen-activated protein kinase kinase kinase MLT (MLK-likemitogen-activated protein triple kinase) (Leucine zipper-and sterilealpha motif-containing kinase) (Sterile alpha motif-and leucinezipper-containing kinase AZK) (Mixed lineage kinase-related kinase)(MLK-related kinase) (MRK) (Cervical cancer suppressor gene4 protein);(3395:) mitogen-activated protein kinase-activated protein kinase 2isoform1 [Homo sapiens]; (3396:) mitogen-activated proteinkinase-activated protein kinase 2 isoform2 [Homo sapiens]; (3397:)Mitotic checkpoint serine/threonine-protein kinase BUB1 (hBUB1) (BUB1A);(3398:) mitotic kinase-like protein-1 [Homo sapiens]; (3399:) MitoticKinesin Eg5; (3400:) MLH1+ins1a isoform [Homo sapiens]; (3401:) MLH1-Ex6isoform [Homo sapiens]; (3402:) MLH3 protein [Homo sapiens]; (3403:)MMS2 [Homo sapiens]; (3404:) MOCS1 [Homo sapiens]; (3405:) MOCS1 protein[Homo sapiens]; (3406:) MOCS1A enzyme [Homo sapiens]; (3407:) MOCS1Aprotein [Homo sapiens]; (3408:) Molybdenum cofactor biosynthesis protein1 A (MOCS1A); (3409:) Molybdenum cofactor biosynthesis protein 1 B(MOCS1B) (Molybdenum cofactor synthesis-step 1 protein A-B) (Molybdenumcofactor biosynthesis protein C); (3410:) molybdenum cofactorbiosynthesis protein A [Homo sapiens]; (3411:) molybdenum cofactorsynthesis-step 1 protein isoform 1 [Homo sapiens]; (3412:) molybdenumcofactor synthesis-step 1 protein isoform 2 [Homo sapiens]; (3413:)molybdenum cofactor synthesis-step 1 protein isoform 3 [Homo sapiens];(3414:) molybdenum cofactor synthesis-step 1 protein isoform 4 [Homosapiens]; (3415:) molybdopterin synthase large subunit MOCS2B [Homosapiens]; (3416:) molybdopterin synthase small subunit MOCS2A [Homosapiens]; (3417:) monoacylglycerol O-acyltransferase 3 [Homo sapiens];(3418:) Monoamine Oxidase A (MAO-A); (3419:) monoamine oxidase A [Homosapiens]; (3420:) Monoamine Oxidase B (MAO-B); (3421:) MonocyteChemoattractant Protein 1 (MCP-1) Receptor; (3422:) Monocyte tomacrophage differentiation factor 2 (Progestin and adipoQ receptorfamily member X); (3423:) Monocyte to macrophage differentiation protein(Progestin and adipoQ receptor family member XI); (3424:) MOP-4 [Homosapiens]; (3425:) mosaic serine protease [Homo sapiens]; (3426:) MotilinReceptor; (3427:) Motilin receptor (G-protein coupled receptor 38);(3428:) M-phase inducer phosphatase 1 (Dual specificity phosphataseCdc25A); (3429:) M-phase inducer phosphatase 2 (Dual specificityphosphatase Cdc25B); (3430:) MRIT-alpha-1 [Homo sapiens]; (3431:) mRNA(guanine-7-)methyltransferase [Homo sapiens]; (3432:) mRNA 5′ capguanine-N-7 methyltransferase [Homo sapiens]; (3433:) mRNA capguanine-N7 methyltransferase (mRNA(guanine-N(7)-)-methyltransferase)(RG7MT1) (mRNA capmethyltransferase) (hcm1p) (hCMT1) (hMet); (3434:)“mRNA capping enzyme (HCE) (HCAP1) [Includes:) Polynucleotide5′-triphosphatase (mRNA 5′-triphosphatase) (TPase); mRNAguanylyltransferase (GTP-RNA guanylyltransferase) (GTase)].”; (3435:)mRNA capping enzyme [Homo sapiens]; (3436:) mRNA decapping enzyme [Homosapiens]; (3437:) mRNA decapping enzyme 1A (Transcription factor SMIF)(Smad-4-interacting transcriptional co-activator); (3438:) mRNAdecapping enzyme 1B; (3439:) mRNA decapping enzyme 2 (hDpc) (Nucleosidediphosphate-linked moiety X motif 20) (Nudix motif 20); (3440:) mRNAdecapping enzyme variant [Homo sapiens]; (3441:) mRNA-decapping enzyme[Homo sapiens]; (3442:) MSTP042 [Homo sapiens]; (3443:) MTO1 isoform[Homo sapiens]; (3444:) MTO1 isoform 2 [Homo sapiens]; (3445:) MTO1protein [Homo sapiens]; (3446:) MTO1 protein isoform III [Homo sapiens];(3447:) MTO1 protein isoform IV [Homo sapiens]; (3448:) MTO1-likeprotein [Homo sapiens]; (3449:) mucin 1 isoform 1 precursor [Homosapiens]; (3450:) mucin 1 isoform 2 precursor [Homo sapiens]; (3451:)mucin 1 isoform 3 precursor [Homo sapiens]; (3452:) mucin 1 isoform 5precursor [Homo sapiens]; (3453:) mucin 1 isoform 6 precursor [Homosapiens]; (3454:) mucin 1 isoform 7 precursor [Homo sapiens]; (3455:)mucin 1 isoform 8 precursor [Homo sapiens]; (3456:) Mucin-1 (MUC1)Glycoprotein; (3457:) mu-crystallin [Homo sapiens]; (3458:)Mu-crystallin homolog (NADP-regulated thyroid-hormone-binding protein);(3459:) Multidrug Resistance-Associated Protein 1 (MRP1); (3460:)Multidrug resistance-associated protein 7 (ATP-binding cassettesub-family C member 10); (3461:) multifunctional protein CAD [Homosapiens]; (3462:) multiple exostoses-like 2 [Homo sapiens]; (3463:)Mu-Opioid Receptor; (3464:) Muscarinic acetylcholine receptor M1;(3465:) Muscarinic acetylcholine receptor M2; (3466:) Muscarinicacetylcholine receptor M3; (3467:) Muscarinic acetylcholine receptor M4;(3468:) Muscarinic acetylcholine receptor M5; (3469:) Muscarinic M1Receptor; (3470:) Muscarinic M2 Receptor; (3471:) Muscarinic M3Receptor; (3472:) Muscarinic M4 Receptor; (3473:) muscle beta 1 integrincytoplasmic domain binding protein MIBP [Homo sapiens]; (3474:) musclecreatine kinase [Homo sapiens]; (3475:) Muscle, skeletal receptortyrosine protein kinase precursor (Muscle-specific tyrosine proteinkinase receptor) (Muscle-specific kinase receptor) (MuSK); (3476:)mutant arylamine N-acetyltransferase [Homo sapiens]; (3477:) mutant 1beta-1,6-N-acetylglucosaminyltransferase C form [Homo sapiens]; (3478:)mutL 3 homolog (E. coli) [Homo sapiens]; (3479:) MutL homolog 1, coloncancer, nonpolyposis type 2 (E. coli) [Homo sapiens]; (3480:) MutLhomolog 3 (E. coli) [Homo sapiens]; (3481:) mutL homolog 3 isoform 1[Homo sapiens]; (3482:) mutL homolog 3 isoform 2 [Homo sapiens]; (3483:)MutL protein homolog 1 [Homo sapiens]; (3484:) MutL protein homolog 1variant [Homo sapiens]; (3485:) mutS homolog 2 [Homo sapiens]; (3486:)mutS homolog 6 [Homo sapiens]; (3487:) mutY homolog isoform 1 [Homosapiens]; (3488:) mutY homolog isoform 2 [Homo sapiens]; (3489:) mutYhomolog isoform 3 [Homo sapiens]; (3490:) mutY homolog isoform 4 [Homosapiens]; (3491:) Mu-type opioid receptor (MOR-1); (3492:) MycobacterialArabinosyltransferases; (3493:) Mycobacterial Fatty Acid Synthetase I(FAS-I); (3494:) Mycobacterial Translocase I; (3495:) MycobacteriumTuberculosis Adenosine Triphosphate (ATP) Synthase; (3496:)Mycobacterium Tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA);(3497:) Mycobacterium Tuberculosis Isocitrate Lyase (Icl); (3498:)myelin basic protein isoform 1 [Homo sapiens]; (3499:) myelin basicprotein isoform 2 [Homo sapiens]; (3500:) myelin basic protein isoform 3[Homo sapiens]; (3501:) myelin basic protein isoform 4 [Homo sapiens];(3502:) myelin basic protein isoform 5 [Homo sapiens]; (3503:) myelinbasic protein isoform 6 [Homo sapiens]; (3504:) Myelin Basic ProteinStimulator; (3505:) Myeloblastin precursor (Leukocyte proteinase 3)(PR-3) (PR3) (AGP7) (Wegener autoantigen) (P29) (C-ANCA antigen)(Neutrophil proteinase 4) (NP-4); (3506:) myelodysplastic syndromesrelative [Homo sapiens]; (3507:) myeloperoxidase [Homo sapiens]; (3508:)myofibrillogenesis regulator 1 isoform 1 [Homo sapiens]; (3509:)myofibrillogenesis regulator 1 isoform 2 [Homo sapiens]; (3510:)myofibrillogenesis regulator 1 isoform 3 [Homo sapiens]; (3511:)myo-inositol oxygenase [Homo sapiens]; (3512:) myo-inositol-1 (or4)-monophosphatase [Homo sapiens]; (3513:) Myosin heavy chain, cardiacmuscle beta isoform (MyHC-beta); (3514:) myosin light chain kinaseisoform 1 [Homo sapiens]; (3515:) myosin light chain kinase isoform 2[Homo sapiens]; (3516:) myosin light chain kinase isoform 3A [Homosapiens]; (3517:) myosin light chain kinase isoform 3B [Homo sapiens];(3518:) Myosin light chain kinase, smooth muscle (MLCK) (Telokin)(Kinase-related protein) (KRP); (3519:) Myosin regulatory light chain 2,nonsarcomeric (Myosin RLC); (3520:) Myosin regulatory light chain 2,smooth muscle isoform (Myosin RLC) (Myosin regulatory light chain 9)(LC20); (3521:) Myostatin; (3522:) myotonic dystrophy protein kinase[Homo sapiens]; (3523:) Myotonin-protein kinase (Myotonic dystrophyprotein kinase) (MDPK) (DM-kinase) (DMK) (DMPK) (MT-PK); (3524:)myristoyl CoA:protein N-myristoyltransferase [Homo sapiens]; (3525:)Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS); (3526:)myristoylated alanine-rich protein kinase C substrate [Homo sapiens];(3527:) myristoyl-CoA:protein N-myristoyltransferase [Homo sapiens];(3528:) Na+/K+-ATPase alpha 1 subunit isoform a proprotein [Homosapiens]; (3529:) Na+/K+-ATPase alpha 1 subunit isoform b proprotein[Homo sapiens]; (3530:) Na+/K+-ATPase alpha 2 subunit proprotein [Homosapiens]; (3531:) Na+/K+-ATPase alpha 3 subunit [Homo sapiens]; (3532:)Na+/K+-ATPase alpha 4 subunit isoform 1 [Homo sapiens]; (3533:)Na+/K+-ATPase alpha 4 subunit isoform 2 [Homo sapiens]; (3534:)Na+/K+-ATPase beta 1 subunit isoform a [Homo sapiens]; (3535:)Na+/K+-ATPase beta 1 subunit isoform b [Homo sapiens]; (3536:)Na+/K+-ATPase beta 2 subunit [Homo sapiens]; (3537:) Na+/K+-ATPase beta3 subunit [Homo sapiens]; (3538:) N-acetylated-alpha-linked acidicdipeptidase 2(N-acetylated-alpha-linked acidic dipeptidase II)(NAALADase II); (3539:) N-acetylated-alpha-linked-acidic dipeptidase(NAALADase); (3540:) N-acetylgalactosamine 4-sulfate6-O-sulfotransferase (GalNAc4S-6ST) (B-cell RAG-associated gene protein)(hBRAG); (3541:) N-acetylgalactosamine 6-sulfate sulfatase [Homosapiens]; (3542:) N-acetylgalactosamine-6-sulfatase precursor [Homosapiens]; (3543:) N-acetylgalactosaminyltransferase 7(Protein-UDPacetylgalactosaminyltransferase 7) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 7) (Polypeptide GalNActransferase 7)(GalNAc-T7) (pp-GaNTase 7); (3544:) N-Acetylglucosamine kinase [Homosapiens]; (3545:) N-acetylglucosamine-1-phosphate transferase [Homosapiens]; (3546:) N-acetylglucosamine-1-phosphodiesteralpha-N-acetylglucosaminidase precursor (Phosphodiester alpha-GlcNAcase)(Mannose6-phosphate-uncovering enzyme); (3547:)N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidaseprecursor [Homo sapiens]; (3548:)N-acetylglucosamine-1-phosphotransferase subunit gamma precursor(GlcNAc-1-phosphotransferase subunit gamma)(UDP-N-acetylglucosamine-1-phosphotransferase, subunit gamma); (3549:)“N-acetylglucosamine-1-phosphotransferase subunits alpha/beta precursor(GlcNAc-1-phosphotransferase alpha/beta subunits)(UDP-N-acetylglucosamine-1-phosphotransferase alpha/beta subunits)(Stealth protein GNPTAB)[Contains:N-acetylglucosamine-1-phosphotransferase subunit alpha;N-acetylglucosamine-1-phosphotransferase subunit beta].”; (3550:)N-acetylglucosamine-1-phosphotransferase, gamma subunit [Homo sapiens];(3551:) N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST) [Homosapiens]; (3552:) N-acetylglutamate synthase [Homo sapiens]; (3553:)“N-acetylglutamate synthase, mitochondrial precursor (Amino-acidacetyltransferase) [Contains:) N-acetylglutamate synthase long form;N-acetylglutamate synthase short form; N-acetylglutamate synthaseconserved domain form].”; (3554:) N-acetyllactosaminidebeta-1,3-N-acetylglucosaminyltransferase (Poly-N-acetyllactosamineextension enzyme) (1-beta-1,3-N-acetylglucosaminyltransferase) (iGnT)(UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 6); (3555:)N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase(N-acetylglucosaminyltransferase) (1-branching enzyme) (IGNT); (3556:)N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase [Homosapiens]; (3557:) N-acetylneuraminate pyruvate lyase [Homo sapiens];(3558:) N-acetylneuraminic acid phosphate synthase [Homo sapiens];(3559:) N-acetyltransferase 1 [Homo sapiens]; (3560:)N-acetyltransferase 2 [Homo sapiens]; (3561:) N-acetyltransferase ESCO1(Establishment of cohesion 1 homolog 1) (ECO1 homolog 1) (ESO1homolog 1) (Establishment factor-like protein 1) (EFO1p) (hEFO1) (CTF7homolog 1); (3562:) N-acylaminoacyl-peptide hydrolase [Homo sapiens];(3563:) N-acylethanolamine-hydrolyzing acid amidase precursor(N-acylsphingosine amidohydrolase-like) (ASAH-like protein)(Acidceramidase-like protein); (3564:) N-acylglucosamine 2-epimerase(GlcNAc 2-epimerase) (N-acetyl-D-glucosamine 2-epimerase) (AGE)(Renin-binding protein) (RnBP); (3565:) N-acyineuraminatecytidylyltransferase (CMP-N-acetylneuraminic acid synthetase)(CMP-NeuNAc synthetase); (3566:) N-acylneuraminate-9-phosphatase(Neu5Ac-9-Pase) (Haloacid dehalogenase-like hydrolase domain-containingprotein 4); (3567:) N-acylsphingosine amidohydrolase (acid ceramidase) 1isoform b[Homo sapiens]; (3568:) N-acylsphingosine amidohydrolase (acidceramidase) 1 preproprotein isoform a [Homo sapiens]; (3569:)N-acylsphingosine amidohydrolase 3 [Homo sapiens]; (3570:)N-acylsphingosine amidohydrolase-like protein isoform 1 precursor[Homosapiens]; (3571:) N-acylsphingosine amidohydrolase-like protein isoform2 precursor[Homo sapiens]; (3572:) NAD kinase (Poly(P)/ATP NAD kinase);(3573:) NAD(P) dependent steroid dehydrogenase-like [Homo sapiens];(3574:) NAD(P)H dehydrogenase [quinone] 1 (Quinone reductase 1)(NAD(P)H:quinone oxidoreductase 1) (QR1) (DT-diaphorase) (DTD)(Azoreductase) (Phylloquinone reductase) (Menadione reductase); (3575:)NAD(P)H menadione oxidoreductase 1, dioxin-inducible isoform a[Homosapiens]; (3576:) NAD(P)H menadione oxidoreductase 1, dioxin-inducibleisoform b[Homo sapiens]; (3577:) NAD(P)H menadione oxidoreductase 1,dioxin-inducible isoform c[Homo sapiens]; (3578:)NAD+ADP-ribosyltransferase; (3579:) NAD-dependent deacetylase sirtuin-1(hSIRT1) (hSIR2) (SIR2-like protein 1); (3580:) NAD-dependentdeacetylase sirtuin-2 (SIR2-like) (SIR2-like protein2); (3581:)NAD-dependent deacetylase sirtuin-3, mitochondrial precursor (SIR2-likeprotein 3) (hSIRT3); (3582:) NAD-dependent malic enzyme, mitochondrialprecursor (NAD-ME) (Malic enzyme 2); (3583:) NADH dehydrogenase(ubiquinone) 1 alpha subcomplex, 10, 42 kDa precursor [Homo sapiens];(3584:) NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9 kDa[Homo sapiens]; (3585:) NADH dehydrogenase (ubiquinone) 1 alphasubcomplex, 5 [Homo sapiens]; (3586:) NADH dehydrogenase (ubiquinone) 1alpha subcomplex, 8, 19 kDa [Homo sapiens]; (3587:) NADH dehydrogenase(ubiquinone) 1 beta subcomplex, 2, 8 kDa precursor [Homo sapiens];(3588:) NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12 kDa[Homo sapiens]; (3589:) NADH dehydrogenase (ubiquinone) 1 betasubcomplex, 4, 15 kDa [Homo sapiens]; (3590:) NADH dehydrogenase(ubiquinone) 1 beta subcomplex, 5, 16 kDa precursor [Homo sapiens];(3591:) NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6,17 kDaisoform 1 [Homo sapiens]; (3592:) NADH dehydrogenase (ubiquinone) 1 betasubcomplex, 6, 17 kDa isoform2 [Homo sapiens]; (3593:) NADHdehydrogenase (ubiquinone) 1 beta subcomplex, 7, 18 kDa [Homo sapiens];(3594:) NADH dehydrogenase (ubiquinone) Fe—S protein 1, 75 kDaprecursor[Homo sapiens]; (3595:) NADH dehydrogenase (ubiquinone) Fe—Sprotein 3, 30 kDa (NADH-coenzyme Q reductase) [Homo sapiens]; (3596:)NADH dehydrogenase (ubiquinone) Fe—S protein 4, 18 kDa (NADH-coenzyme Qreductase) [Homo sapiens]; (3597:) NADH dehydrogenase (ubiquinone) Fe—Sprotein 6, 13 kDa (NADH-coenzyme Q reductase) [Homo sapiens]; (3598:)NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1(NADH-ubiquinone oxidoreductase MWFE subunit) (Complex I-MWFE)(CI-MWFE); (3599:) NADH dehydrogenase [ubiquinone] 1 alpha subcomplexsubunit 10, mitochondrial precursor (NADH-ubiquinone oxidoreductase 42kDa subunit) (Complex I-42 kD) (CI-42 kD); (3600:) NADH dehydrogenase[ubiquinone] 1 alpha subcomplex subunit 11 (NADH-ubiquinoneoxidoreductase subunit B14.7) (Complex I-B14.7) (C1-B14.7); (3601:) NADHdehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12(NADH-ubiquinoneoxidoreductase subunit B17.2) (Complex I-B17.2) (C1-B17.2) (CIB17.2) (13kDa differentiation-associated protein); (3602:) NADH dehydrogenase[ubiquinone] 1 alpha subcomplex subunit 13(NADH-ubiquinoneoxidoreductase B16.6 subunit) (Complex I-B16.6) (CI-B16.6) (Geneassociated with retinoic-interferon-induced mortality 19 protein)(GRIM-19) (Cell death-regulatory protein GRIM-19); (3603:) NADHdehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2(NADH-ubiquinoneoxidoreductase B8 subunit) (Complex I-B8) (C1-B8); (3604:) NADHdehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3(NADH-ubiquinoneoxidoreductase B9 subunit) (Complex I-B9) (C1-B9); (3605:) NADHdehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4(NADH-ubiquinoneoxidoreductase MLRQ subunit) (Complex I-MLRQ) (CI-MLRQ); (3606:) NADHdehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5(NADH-ubiquinoneoxidoreductase 13 kDa-B subunit) (Complex I-13 kD-B) (CI-13 kD-B)(Complex I subunit B13); (3607:) NADH dehydrogenase [ubiquinone] 1 alphasubcomplex subunit 6(NADH-ubiquinone oxidoreductase B14 subunit)(Complex I-B14) (CI-B14); (3608:) NADH dehydrogenase [ubiquinone] 1alpha subcomplex subunit 7(NADH-ubiquinone oxidoreductase subunitB14.5a) (Complex I-B14.5a) (CI-B14.5a); (3609:) NADH dehydrogenase[ubiquinone] 1 alpha subcomplex subunit 8(NADH-ubiquinone oxidoreductase19 kDa subunit) (Complex I-19 kD) (CI-19 kD) (Complex I-PGIV) (CI-PGIV);(3610:) NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9,mitochondrial precursor (NADH-ubiquinone oxidoreductase 39 kDa subunit)(Complex I-39 kD) (CI-39 kD); (3611:) NADH dehydrogenase [ubiquinone] 1beta subcomplex subunit 1(NADH-ubiquinone oxidoreductase MNLL subunit)(Complex I-MNLL) (CI-MNLL); (3612:) NADH dehydrogenase [ubiquinone] 1beta subcomplex subunit 10(NADH-ubiquinone oxidoreductase PDSW subunit)(Complex I-PDSW) (CI-PDSW); (3613:) NADH dehydrogenase [ubiquinone] 1beta subcomplex subunit 11, mitochondrial precursor (NADH-ubiquinoneoxidoreductase ESSS subunit) (Complex I-ESSS) (CI-ESSS) (Neuronalprotein 17.3) (p17.3) (Np17.3); (3614:) NADH dehydrogenase [ubiquinone]1 beta subcomplex subunit 2, mitochondrial precursor (NADH-ubiquinoneoxidoreductase AGGG subunit) (Complex I-AGGG) (CI-AGGG); (3615:) NADHdehydrogenase [ubiquinone] 1 beta subcomplex subunit 3(NADH-ubiquinoneoxidoreductase B12 subunit) (Complex I-B12) (CI-B12); (3616:) NADHdehydrogenase [ubiquinone] 1 beta subcomplex subunit 4(NADH-ubiquinoneoxidoreductase B15 subunit) (Complex I-B15) (CI-B15); (3617:) NADHdehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrialprecursor (NADH-ubiquinone oxidoreductase SGDH subunit) (Complex I-SGDH)(CI-SGDH); (3618:) NADH dehydrogenase [ubiquinone] 1 beta subcomplexsubunit 6(NADH-ubiquinone oxidoreductase B17 subunit) (Complex I-B17)(CI-B17); (3619:) NADH dehydrogenase [ubiquinone] 1 beta subcomplexsubunit 7(NADH-ubiquinone oxidoreductase B18 subunit) (Complex I-B18)(CI-B18) (Cell adhesion protein SQM1); (3620:) NADH dehydrogenase[ubiquinone] 1 beta subcomplex subunit 8, mitochondrial precursor(NADH-ubiquinone oxidoreductase ASHI subunit) (Complex I-ASHI)(CI-ASHI); (3621:) NADH dehydrogenase [ubiquinone] 1 beta subcomplexsubunit 9(NADH-ubiquinone oxidoreductase B22 subunit) (Complex I-B22)(CI-B22); (3622:) NADH dehydrogenase [ubiquinone] 1 subunit C1,mitochondrial precursor (NADH-ubiquinone oxidoreductase KFYI subunit)(ComplexI-KFYI) (CI-KFYI); (3623:) NADH dehydrogenase [ubiquinone] 1subunit C2 (NADH-ubiquinoneoxido reductase subunit B14.5b) (ComplexI-BI4.5b) (CI-B14.5b); (3624:) NADH dehydrogenase [ubiquinone]flavoprotein 1, mitochondrial precursor (NADH-ubiquinone oxidoreductase51 kDa subunit) (ComplexI-51 kD) (CI-51 kD) (NADH dehydrogenaseflavoprotein 1); (3625:) NADH dehydrogenase [ubiquinone] flavoprotein 2,mitochondrial precursor (NADH-ubiquinone oxidoreductase 24 kDa subunit);(3626:) NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrialprecursor (NADH-ubiquinone oxidoreductase 9 kDa subunit) (ComplexI-9 kD)(C₁₋₉ kD) (NY-REN-4 antigen); (3627:) NADH dehydrogenase [ubiquinone]iron-sulfur protein 2, mitochondrial precursor (NADH-ubiquinoneoxidoreductase 49 kDa subunit) (Complex I-49 kD) (CI-49 kD); (3628:)NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrialprecursor (NADH-ubiquinone oxidoreductase 30 kDa subunit) (Complex I-30kD) (CI-30 kD); (3629:) NADH dehydrogenase [ubiquinone] iron-sulfurprotein 4, mitochondrial precursor (NADH-ubiquinone oxidoreductase 18kDa subunit) (Complex I-18 kDa) (CI-18 kDa) (Complex I-AQDQ) (CI-AQDQ);(3630:) NADH dehydrogenase [ubiquinone] iron-sulfur protein5(NADH-ubiquinone oxidoreductase 15 kDa subunit) (Complex I-15 kDa)(CI-15 kDa); (3631:) NADH dehydrogenase [ubiquinone] iron-sulfur protein6, mitochondrial precursor (NADH-ubiquinone oxidoreductase 13 kDa-Asubunit) (Complex I-13 kD-A) (CI-13 kD-A); (3632:) NADH dehydrogenase[ubiquinone] iron-sulfur protein 7, mitochondrial precursor(NADH-ubiquinone oxidoreductase 20 kDa subunit) (Complex I-20 kD) (CI-20kD) (PSST subunit); (3633:) “NADH-cytochrome b5 reductase (B5R)(Diaphorase-1) (Cytochrome b5reductase 3) [Contains:) NADH-cytochrome b5reductase membrane-bound form; NADH-cytochrome b5 reductase solubleform].”; (3634:) NADH-cytochrome b5 reductase [Homo sapiens]; (3635:)“NADH-cytochrome b5 reductase; b5R [Homo sapiens].”; (3636:)NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial precursor(Complex I-75 kD) (C1-75 kD); (3637:) NADP(+)-dependent malicenzyme—human (fragments); (3638:) “NADP+-dependent malic enzyme; malatedehydrogenase (oxaloacetate decarboxylating) (NADP+) [Homo sapiens].”;(3639:) NADP-dependent isocitrate dehydrogenase [Homo sapiens]; (3640:)NADP-dependent malic enzyme (NADP-ME) (Malic enzyme 1); (3641:)NADP-dependent malic enzyme, mitochondrial precursor (NADP-ME) (Malicenzyme 3); (3642:) NADP-dependent malic enzyme; (3643:) NADPH oxidase 1isoform long [Homo sapiens]; (3644:) NADPH oxidase 1 isoform longvariant [Homo sapiens]; (3645:) NADPH oxidase 1 isoform short [Homosapiens]; (3646:) NADPH oxidase 3 (gp91phox homolog 3) (GP91-3)(Mitogenic oxidase 2); (3647:) NADPH oxidase 3 [Homo sapiens]; (3648:)NADPH oxidase 4 (Kidney superoxide-producing NADPH oxidase) (KOX-1)(Renal NAD(P)H-oxidase); (3649:) NADPH oxidase 5; (3650:) NADPH oxidasehomolog 1 (NOX-1) (NOH-1) (NADH/NADPH mitogenic oxidase subunit P65-MOX)(Mitogenic oxidase 1) (MOX1); (3651:) NADPH oxidase, EF handcalcium-binding domain 5 [Homo sapiens]; (3652:) NADPH—cytochrome P450reductase (CPR) (P450R); (3653:) nardilysin (N-arginine dibasicconvertase) [Homo sapiens]; (3654:) Nardilysin precursor (N-argininedibasic convertase) (NRD convertase) (NRD-C); (3655:) N-arginine dibasicconvertase [Homo sapiens]; (3656:) natriuretic peptide precursor A [Homosapiens]; (3657:) natriuretic peptide precursor B preproprotein [Homosapiens]; (3658:) Natriuretic Peptide Receptor A (NPR-A); (3659:)natriuretic peptide receptor A/guanylate cyclase A (atrionatriureticpeptide receptor A) [Homo sapiens]; (3660:) natriuretic peptide receptorB precursor [Homo sapiens]; (3661:) Natural cytotoxicity triggeringreceptor 1 precursor (Natural killer cell p46-related protein) (NKp46)(hNKp46) (NK-p46) (NK cell-activating receptor) (Lymphocyte antigen 94homolog) (CD335antigen); (3662:) Natural cytotoxicity triggeringreceptor 2 precursor (Natural killer cell p44-related protein) (NKp44)(NK-p44) (NK cell-activating receptor) (Lymphocyte antigen 95 homolog)(CD336antigen); (3663:) Natural cytotoxicity triggering receptor 3precursor (Natural killer cell p30-related protein) (NKp30) (NK-p30)(CD337 antigen); (3664:) Natural killer cell receptor 2B4 precursor(NKR2B4) (NK cell type I receptor protein 2B4) (h2B4) (CD244 antigen)(NK cell activation-inducing ligand) (NAIL); (3665:) Natural killercells antigen CD94 (NK cell receptor) (Killer cell lectin-like receptorsubfamily D member 1) (KP43); (3666:) N-Cadherin; (3667:) NCUBE1 [Homosapiens]; (3668:) N-deacetylase/N-sulfotransferase (heparanglucosaminyl)₂ [Homo sapiens]; (3669:) NDUFS1 protein [Homo sapiens];(3670:) NEDD4-like E3 ubiquitin-protein ligase WWP1 (WWdomain-containing protein 1) (Atropin-1-interacting protein 5) (AIP5);(3671:) NEDD4-like E3 ubiquitin-protein ligase WWP2 (WWdomain-containing protein 2) (Atrophin-1-interacting protein 2) (AIP2);(3672:) NEDD8 precursor (Ubiquitin-like protein Nedd8) (Neddylin);(3673:) NEDD8-activating enzyme E1 catalytic subunit(Ubiquitin-activating enzyme 3) (NEDD8-activating enzyme E1C)(Ubiquitin-activating enzyme E1C); (3674:) NEDD8-activating enzyme E1regulatory subunit (Amyloid protein-binding protein 1) (Amyloid betaprecursor protein-binding protein 1, 59 kDa) (APP-BP1) (Protooncogeneprotein 1) (HPP1); (3675:) Nedd8-activating enzyme hUba3 [Homo sapiens];(3676:) NEDD8-conjugating enzyme [Homo sapiens]; (3677:)Nedd8-conjugating enzyme hUbc12 [Homo sapiens]; (3678:)NEDD8-conjugating enzyme NCE2 [Homo sapiens]; (3679:) NEDD8-conjugatingenzyme Ubc12 (Ubiquitin-conjugating enzyme E2 M) (NEDD8 protein ligase)(NEDD8 carrier protein); (3680:) Nef associated protein 1 [Homosapiens]; (3681:) nei endonuclease VIII-like 1 [Homo sapiens]; (3682:)nei-like 2 [Homo sapiens]; (3683:) Nematode Nicotinic AcetylcholineReceptor (nAChR); (3684:) neo-poly(A) polymerase [Homo sapiens]; (3685:)nephrin [Homo sapiens]; (3686:) Nerve Growth Factor (NGF); (3687:)Netrin receptor DCC precursor (Tumor suppressor protein DCC) (Colorectalcancer suppressor); (3688:) Netrin receptor UNC5A precursor (Unc-5homolog A) (Unc-5 homolog1); (3689:) Netrin receptor UNC5B precursor(Unc-5 homolog B) (Unc-5 homolog 2) (p53-regulated receptor for deathand life protein 1); (3690:) Netrin receptor UNC5C precursor (Unc-5homolog C) (Unc-5 homolog3); (3691:) Netrin receptor UNC5D precursor(Unc-5 homolog D) (Unc-5 homolog4); (3692:) neural stem cell-deriveddendrite regulator [Homo sapiens]; (3693:) Neural Thread Protein (NTP);(3694:) Neutralized-like protein 2; (3695:) Neuraminidase; (3696:)neuraminidase precursor [Homo sapiens]; (3697:) neuroblastomaapoptosis-related protease [Homo sapiens]; (3698:) Neuroendocrineconvertase 1 precursor (NEC 1) (PC1) (Prohormone convertase 1)(Proprotein convertase 1); (3699:) Neuroendocrine convertase 2 precursor(NEC 2) (PC2) (Prohormone convertase 2) (Proprotein convertase 2)(KEX2-like endoprotease 2); (3700:) Neurofibromin(Neurofibromatosis-related protein NF-1) [Contains:Neurofibromintruncated]; (3701:) neurofibromin isoform 1 [Homo sapiens]; (3702:)neurofibromin isoform 2 [Homo sapiens]; (3703:) neurofilament, lightpolypeptide 68 kDa [Homo sapiens]; (3704:) “Neurogenic locus notchhomolog protein 1 precursor (Notch 1) (hN1) (Translocation-associatednotch protein TAN-1) [Contains:) Notch 1 extracellular truncation; Notch1 intracellular domain].”; (3705:) “Neurogenic locus notch homologprotein 2 precursor (Notch 2) (hN2)[Contains:) Notch 2 extracellulartruncation; Notch 2 intracellular domain].”; (3706:) “Neurogenic locusnotch homolog protein 3 precursor (Notch 3)[Contains:) Notch 3extracellular truncation; Notch 3 intracellular domain].”; (3707:)“Neurogenic locus notch homolog protein 4 precursor (Notch 4) (hNotch4)[Contains:) Notch 4 extracellular truncation; Notch 4 intracellulardomain].”; (3708:) Neurokinin NK1 Receptor; (3709:) Neurokinin NK2Receptor; (3710:) Neurokinin NK3 Receptor; (3711:) Neuromedin K receptor(NKR) (Neurokinin B receptor) (NK-3 receptor) (NK-3R) (Tachykininreceptor 3); (3712:) Neuromedin U receptor 1 (NMU-R1) (G-protein coupledreceptor 66) (G-protein coupled receptor FM-3); (3713:) Neuromedin Ureceptor 2 (NMU-R2) (G-protein coupled receptor TGR-1) (G-proteincoupled receptor FM-4); (3714:) Neuromedin-B receptor (NMB-R)(Neuromedin-B-preferring bombesin receptor); (3715:) Neuronalacetylcholine receptor protein subunit alpha-10 precursor (Nicotinicacetylcholine receptor subunit alpha 10) (NACHR alpha10); (3716:)Neuronal acetylcholine receptor protein subunit alpha-3 precursor;(3717:) Neuronal acetylcholine receptor protein subunit alpha-5precursor; (3718:) Neuronal acetylcholine receptor protein subunitalpha-6 precursor; (3719:) Neuronal acetylcholine receptor proteinsubunit alpha-9 precursor (Nicotinic acetylcholine receptor subunitalpha 9) (NACHR alpha 9); (3720:) Neuronal Nicotinic AcetylcholineReceptor (nAChR); (3721:) Neuronal pentraxin receptor; (3722:) neuronaltryptophan hydroxylase [Homo sapiens]; (3723:) neuron-derived receptorNOR-1—human; (3724:) Neuropeptide FF receptor 1 (G-protein coupledreceptor 147) (RF amide-related peptide receptor OT7T022); (3725:)Neuropeptide FF receptor 2 (Neuropeptide G-protein coupled receptor)(G-protein coupled receptor 74) (G-protein coupled receptor HLWAR77);(3726:) Neuropeptide S receptor (G-protein coupled receptor 154)(G-protein coupled receptor for asthma susceptibility) (G-proteincoupled receptor PGR14); (3727:) Neuropeptide Y receptor type 1(NPY1-R); (3728:) Neuropeptide Y receptor type 2 (NPY2-R) (NPY-Y2receptor); (3729:) Neuropeptide Y receptor type 4 (NPY4-R) (Pancreaticpolypeptide receptor 1) (PP1); (3730:) Neuropeptide Y receptor type 5(NPY5-R) (NPY-Y5 receptor) (Y5receptor) (NPYY5); (3731:) Neuropeptide YY1 Receptor (NPY Y1R); (3732:) Neuropeptide Y Y2 Receptor (NPY Y2R);(3733:) Neuropeptide Y Y4 Receptor (NPY Y4R); (3734:) Neuropeptide Y Y5Receptor (NPY Y5R); (3735:) Neuropeptides B/W receptor type 1 (G-proteincoupled receptor 7); (3736:) Neuropeptides B/W receptor type 2(G-protein coupled receptor 8); (3737:) Neuropilin and tolloid-likeprotein 1 precursor (Brain-specific transmembrane protein containing 2CUB and 1 LDL-receptor class A domains protein 1); (3738:) Neuropilinand tolloid-like protein 2 precursor (Brain-specific transmembraneprotein containing 2 CUB and 1 LDL-receptor class A domains protein 2);(3739:) Neuropilin-1 precursor (Vascular endothelial cell growth factor165receptor) (CD304 antigen); (3740:) Neuropilin-2 precursor (Vascularendothelial cell growth factor 165receptor 2); (3741:) NeurotensinReceptor; (3742:) Neurotensin receptor type 1 (NT-R-1) (High-affinitylevocabastine-insensitive neurotensin receptor) (NTRH); (3743:)Neurotensin receptor type 2 (NT-R-2) (Levocabastine-sensitiveneurotensin receptor) (NTR2 receptor); (3744:) neurotensin/neuromedin Npreproprotein [Homo sapiens]; (3745:) Neurotrophic factor productionaccelerator; (3746:) Neurotrophic Tyrosine Kinase Receptor 1 (NTRK1);(3747:) Neurotrophic Tyrosine Kinase Receptor 2 (NTRK2); (3748:)neurotrophin 5 preproprotein [Homo sapiens]; (3749:) neurotrypsinprecursor [Homo sapiens]; (3750:) Neutral alpha-glucosidase AB precursor(Glucosidase II subunit alpha); (3751:) Neutral amino acid transporterB(0) (ATB(0)) (Sodium-dependent neutral amino acid transporter type 2)(RD114/simian type Dretrovirus receptor) (Baboon M7 virus receptor);(3752:) Neutral ceramidase (NCDase) (N-CDase) (Acylsphingosine deacylase2) (N-acylsphingosine amidohydrolase 2) (BCDase) (LCDase)(hCD)[Contains:) Neutral ceramidase soluble form]; (3753:) NeutralEndopeptidase (NEP); (3754:) Neutral Sphingomyelinase (nSMase); (3755:)Neutrophil Cathepsin G; (3756:) Neutrophil collagenase precursor (Matrixmetalloproteinase-8) (MMP-8) (PMNL collagenase) (PMNL-CL); (3757:)Neutrophil cytosol factor 4 (NCF-4) (Neutrophil NADPH oxidase factor 4)(p40-phox) (p40phox); (3758:) neutrophil cytosolic factor 1 [Homosapiens]; (3759:) neutrophil cytosolic factor 4 (40 kD) isoform 1 [Homosapiens]; (3760:) neutrophil cytosolic factor 4 (40 kD) isoform 2 [Homosapiens]; (3761:) Neutrophil Elastase; (3762:) NFS1 nitrogen fixation 1[Homo sapiens]; (3763:) “N-glycosylase/DNA lyase [Includes:)8-oxoguanine DNA glycosylase; DNA-(apurinic or apyrimidinic site) lyase(Alyase)].”; (3764:) Niacin Receptor; (3765:) Nicastrin precursor;(3766:) NICE-S protein [Homo sapiens]; (3767:) Nicotinamide AdenineDinucleotide synthetase (NADs); (3768:) nicotinamide mononucleotideadenylyl transferase [Homo sapiens]; (3769:) Nicotinamide mononucleotideadenylyltransferase 1 (NMN adenylyltransferase 1); (3770:) nicotinamidemononucleotide adenylyltransferase 2 isoform 1 [Homo sapiens]; (3771:)nicotinamide mononucleotide adenylyltransferase 2 isoform 2 [Homosapiens]; (3772:) nicotinamide nucleotide adenylyltransferase 1 [Homosapiens]; (3773:) nicotinamide nucleotide adenylyltransferase 3 [Homosapiens]; (3774:) nicotinamide riboside kinase 1 [Homo sapiens]; (3775:)Nicotinamide riboside kinase 2 (Integrin beta-1-binding protein 3)(Muscle integrin-binding protein) (MIBP); (3776:) nicotinamide ribosidekinase 2 [Homo sapiens]; (3777:) Nicotinic acid receptor 1 (G-proteincoupled receptor 109A) (G-protein coupled receptor HM74A); (3778:)Nicotinic acid receptor 2 (G-protein coupled receptor 109B) (G-proteincoupled receptor HM74) (G-protein coupled receptor HM74B); (3779:)Nicotinic Receptor; (3780:) NifU-like N-terminal domain-containingprotein, mitochondrial precursor (NifU-like protein) (Iron-sulfurcluster assembly enzyme ISCU); (3781:) Nitric Oxide Neutralizer; (3782:)Nitric Oxide Synthase (NOS); (3783:) nitric oxide synthase 1 (neuronal)[Homo sapiens]; (3784:) nitric oxide synthase 2A isoform 1 [Homosapiens]; (3785:) nitric oxide synthase 2A isoform 2 [Homo sapiens];(3786:) nitric oxide synthase 3 (endothelial cell) [Homo sapiens];(3787:) nitric oxide synthase trafficking isoform 1 [Homo sapiens];(3788:) nitric oxide synthase trafficking isoform 2 [Homo sapiens];(3789:) Nitric oxide synthase, inducible (NOS type 11) (Inducible NOsynthase) (Inducible NOS) (iNOS) (Hepatocyte NOS) (HEP-NOS); (3790:)nitric oxide synthase; (3791:) Nitric-oxide synthase IIC (NOS type II C)(NOSIIc); (3792:) Nitric-oxide synthase, brain (NOS type 1) (NeuronalNOS) (N-NOS) (nNOS) (Constitutive NOS) (NC-NOS) (bNOS); (3793:)Nitric-oxide synthase, endothelial (EC-NOS) (NOS type II) (NOSII)(Endothelial NOS) (eNOS) (Constitutive NOS) (cNOS); (3794:)NKG2-A/NKG2-B type II integral membrane protein (NKG2-A/B-activating NKreceptor) (NK cell receptor A) (CD159a antigen); (3795:) NKG2-C type IIintegral membrane protein (NKG2-C-activating NK receptor) (NK cellreceptor C) (CD159c antigen); (3796:) NKG2-D type II integral membraneprotein (NKG2-D-activating NK receptor) (NK cell receptor D) (Killercell lectin-like receptor subfamily K member 1) (CD314 antigen); (3797:)NKG2-E type II integral membrane protein (NKG2-E-activating NK receptor)(NK cell receptor E); (3798:) NKG2-F type II integral membrane protein(NKG2-F-activating NK receptor) (NK cell receptor F); (3799:) N-kinase;(3800:) NME1-NME2 protein [Homo sapiens]; (3801:) N-methyl purineDNA-glycosylase [Homo sapiens]; (3802:) N-Methyl-D-Aspartate (NMDA)Receptor; (3803:) N-methylpurine-DNA glycosylase isoform a [Homosapiens]; (3804:) N-methylpurine-DNA glycosylase isoform b [Homosapiens]; (3805:) N-methylpurine-DNA glycosylase isoform c [Homosapiens]; (3806:) N-myristoyltransferase 1 [Homo sapiens]; (3807:)Nociceptin receptor (Orphanin FQ receptor) (Kappa-type 3 opioidreceptor) (KOR-3); (3808:) NOD2 (CARD15) Receptor; (3809:) Non-CanonicalUBiquitin Conjugating Enzyme 1 (NCUBE1) [Homo sapiens]; (3810:)nonfunctional alpha(1,2)-fucosyltransferase [Homo sapiens]; (3811:)non-metastatic cells 1, protein (NM23A) expressed in isoform a[Homosapiens]; (3812:) non-metastatic cells 1, protein (NM23A) expressed inisoform b[Homo sapiens]; (3813:) non-metastatic cells 2, protein (NM23B)expressed in [Homo sapiens]; (3814:) Norepinephrine Reuptake; (3815:)Notch-1 Protein; (3816:) nov precursor [Homo sapiens]; (3817:) novelAMP-binding enzyme [Homo sapiens]; (3818:) novel protein [Homo sapiens];(3819:) N-sulfoglucosamine sulfohydrolase (sulfamidase) [Homo sapiens];(3820:) N-sulphoglucosamine sulphohydrolase [Homo sapiens]; (3821:)N-sulphoglucosamine sulphohydrolase precursor(Sulfoglucosaminesulfamidase) (Sulphamidase); (3822:) NT-3 growth factorreceptor precursor (Neurotrophic tyrosine kinase receptor type 3) (TrkCtyrosine kinase) (GP145-TrkC) (Trk-C); (3823:) N-terminal Asn amidase[Homo sapiens]; (3824:) nth endonuclease III-like 1 [Homo sapiens];(3825:) N-Type Calcium Channel Blocker (NCCB); (3826:) NUAK familySNF1-like kinase 1 (AMPK-related protein kinase 5); (3827:) NUAK familySNF1-like kinase 2 (SNF1/AMP kinase-related kinase) (SNARK); (3828:)nuclear factor (erythroid-derived 2)-like 2 [Homo sapiens]; (3829:)nuclear factor kappa-B, subunit 1 [Homo sapiens]; (3830:) NuclearFactor-Kappa B (NF-kB); (3831:) Nuclear receptor OB1 (Nuclear receptorDAX-1) (DSS-AHC critical region on the X chromosome protein 1); (3832:)Nuclear receptor OB2 (Orphan nuclear receptor SHP) (Small heterodimerpartner); (3833:) Nuclear receptor coactivator 3 (NCoA-3) (Thyroidhormone receptor activator molecule 1) (TRAM-1) (ACTR)(Receptor-associated coactivator 3) (RAC-3) (Amplified in breastcancer-1 protein) (AIB-1) (Steroid receptor coactivator protein 3)(SRC-3) (CBP-interacting protein) (pCIP); (3834:) nuclear receptorinteracting protein 1 [Homo sapiens]; (3835:) Nuclear receptor ROR-alpha(Nuclear receptor RZR-alpha); (3836:) Nuclear receptor ROR-beta (Nuclearreceptor RZR-beta); (3837:) Nuclear receptor ROR-gamma (Nuclear receptorRZR-gamma); (3838:) nuclear receptor subfamily 1, group H, member 4[Homo sapiens]; (3839:) nuclear receptor subfamily 3, group C, member 1isoform alpha [Homo sapiens]; (3840:) nuclear receptor subfamily 3,group C, member 1 isoform beta [Homo sapiens]; (3841:) nuclear receptorsubfamily 3, group C, member 1 isoform gamma [Homo sapiens]; (3842:)nuclear receptor subfamily 5, group A, member 1 [Homo sapiens]; (3843:)nuclear receptor subfamily 5, group A, member 2 isoform 1 [Homosapiens]; (3844:) nuclear receptor subfamily 5, group A, member 2isoform 2 [Homo sapiens]; (3845:) nucleolar protein GU2 [Homo sapiens];(3846:) Nucleolin; (3847:) Nucleoside diphosphate kinase A (NDK A) (NDPkinase A) (Tumor metastatic process-associated protein) (Metastasisinhibition factor nm23) (nm23-H1) (Granzyme A-activated DNase) (GAAD);(3848:) Nucleoside diphosphate kinase B (NDK B) (NDP kinase B) (nm23-H2)(C-myc purine-binding transcription factor PUF); (3849:) NucleosideReverse Transcriptase (NRTI); (3850:) “nucleotide binding protein; NBP[Homo sapiens].”; (3851:) nudix-type motif 14 [Homo sapiens]; (3852:)nudix-type motif 1 isoform p18 [Homo sapiens]; (3853:) nudix-type motif1 isoform p22 [Homo sapiens]; (3854:) nudix-type motif 2 [Homo sapiens];(3855:) 06-Alkylguanine-DNA Alkyltransferase (AGT); (3856:)O-6-methylguanine-DNA methyltransferase; (3857:) OB-Cadherin; (3858:)Olfactory receptor 10A1 (Olfactory receptor 11-403) (OR11-403); (3859:)Olfactory receptor 10A3 (HTPCRX12); (3860:) Olfactory receptor 10A4(HP2) (Olfactory receptor-like protein JCG5); (3861:) Olfactory receptor10A5 (HP3) (Olfactory receptor-like protein JCG6); (3862:) Olfactoryreceptor 10A6; (3863:) Olfactory receptor 10A7; (3864:) Olfactoryreceptor 10AD1; (3865:) Olfactory receptor 10AG1 (Olfactory receptorOR11-160); (3866:) Olfactory receptor 10C1 (Hs6M1-17); (3867:) Olfactoryreceptor 10D4; (3868:) Olfactory receptor 10G2; (3869:) Olfactoryreceptor 10G3 (Olfactory receptor OR14-40); (3870:) Olfactory receptor10G4 (Olfactory receptor OR11-278); (3871:) Olfactory receptor 10G6(Olfactory receptor OR11-280); (3872:) Olfactory receptor 10G7; (3873:)Olfactory receptor 10G8 (Olfactory receptor OR11-282); (3874:) Olfactoryreceptor 10G9; (3875:) Olfactory receptor 10H1; (3876:) Olfactoryreceptor 10H2; (3877:) Olfactory receptor 10H3; (3878:) Olfactoryreceptor 10H4; (3879:) Olfactory receptor 10H5; (3880:) Olfactoryreceptor 10J1 (Olfactory receptor-like protein HGMP07J) (Olfactoryreceptor OR1-26); (3881:) Olfactory receptor 10J3; (3882:) Olfactoryreceptor 10J5; (3883:) Olfactory receptor 10J6; (3884:) Olfactoryreceptor 10K1; (3885:) Olfactory receptor 10K2 (Olfactory receptorOR1-4); (3886:) Olfactory receptor 10P1 (Olfactory receptor OR12-7);(3887:) Olfactory receptor 10Q1; (3888:) Olfactory receptor 10R2;(3889:) Olfactory receptor 10S1; (3890:) Olfactory receptor 10T2(Olfactory receptor OR1-3); (3891:) Olfactory receptor 10V1; (3892:)Olfactory receptor 10W1 (Olfactory receptor OR11-236); (3893:) Olfactoryreceptor 10X1 (Olfactory receptor OR1-14); (3894:) Olfactory receptor10Z1; (3895:) Olfactory receptor 11A1 (Hs6M1-18); (3896:) Olfactoryreceptor 11G2; (3897:) Olfactory receptor 11H1 (Olfactory receptor 22-1)(OR22-1); (3898:) Olfactory receptor 11H4 (Olfactory receptor OR14-36);(3899:) Olfactory receptor 11H6 (Olfactory receptor OR14-35); (3900:)Olfactory receptor 11L1; (3901:) Olfactory receptor 12D2 (Hs6M1-20);(3902:) Olfactory receptor 12D3 (Hs6M1-27); (3903:) Olfactory receptor13A1 (Olfactory receptor OR10-3); (3904:) Olfactory receptor 13C2;(3905:) Olfactory receptor 13C3; (3906:) Olfactory receptor 13C4;(3907:) Olfactory receptor 13C5; (3908:) Olfactory receptor 13C8;(3909:) Olfactory receptor 13C9; (3910:) Olfactory receptor 13D1;(3911:) Olfactory receptor 13F1; (3912:) Olfactory receptor 13G1;(3913:) Olfactory receptor 13H1; (3914:) Olfactory receptor 13J1;(3915:) Olfactory receptor 1A1 (Olfactory receptor 17-7) (OR17-7)(Olfactory receptor OR17-11); (3916:) Olfactory receptor 1A2 (Olfactoryreceptor 17-6) (OR17-6) (Olfactory receptor OR17-10); (3917:) Olfactoryreceptor 1 BI (Olfactory receptor 9-B) (OR9-B) (Olfactory receptorOR9-26); (3918:) Olfactory receptor 1C1 (Olfactory receptor TPCR27)(Olfactory receptor OR1-42); (3919:) Olfactory receptor 1 D2 (Olfactoryreceptor-like protein HGMP07E) (Olfactory receptor 17-4) (OR17-4);(3920:) Olfactory receptor 1 D4 (Olfactory receptor 17-30) (OR17-30);(3921:) Olfactory receptor 1D5 (Olfactory receptor 17-31) (OR17-31);(3922:) Olfactory receptor 1E1 (Olfactory receptor-like protein HGMP071)(Olfactory receptor 17-2/17-32) (OR17-2) (OR17-32) (Olfactory receptor13-66) (OR13-66) (Olfactory receptor 5-85) (OR5-85); (3923:) Olfactoryreceptor 1E2 (Olfactory receptor 17-93/17-135/17-136) (OR17-93)(OR17-135) (OR17-136); (3924:) Olfactory receptor 1F1 (Olfactoryreceptor 16-35) (OR16-35) (Olfactory receptor OR16-4); (3925:) Olfactoryreceptor 1F10 (Olfactory receptor 3-145) (OR3-145); (3926:) Olfactoryreceptor 1F12 (Hs6M1-35P); (3927:) Olfactory receptor 1F2 (OLFmf2);(3928:) Olfactory receptor 1G1 (Olfactory receptor 17-209) (OR17-209);(3929:) Olfactory receptor 111 (Olfactory receptor 19-20) (OR19-20);(3930:) Olfactory receptor 1J1 (Olfactory receptor OR9-18); (3931:)Olfactory receptor 1J2 (OST044) (HSA5) (HTPCRX15) (Olfactory receptorOR9-19); (3932:) Olfactory receptor 1J4 (HTPCRX01) (Olfactory receptorOR9-21); (3933:) Olfactory receptor 1K1; (3934:) Olfactory receptor 1L1(Olfactory receptor 9-C) (OR9-C); (3935:) Olfactory receptor 1 L3(Olfactory receptor 9-D) (OR9-D) (Olfactory receptor OR9-28); (3936:)Olfactory receptor 1 L4 (Olfactory receptor 9-E) (OR9-E) (OST046);(3937:) Olfactory receptor 1 L6; (3938:) Olfactory receptor 1 L8(Olfactory receptor OR9-24); (3939:) Olfactory receptor 1M1 (Olfactoryreceptor 19-6) (OR19-6); (3940:) Olfactory receptor 1N1 (Olfactoryreceptor 1-26) (OR1-26) (Olfactory receptor 1N3) (Olfactory receptorOR9-22); (3941:) Olfactory receptor 1N2; (3942:) Olfactory receptor 1Q1(Olfactory receptor TPCR106) (Olfactory receptor 9-A) (OR9-A) (OST226)(Olfactory receptor OR9-25); (3943:) Olfactory receptor 1S1; (3944:)Olfactory receptor 1S2; (3945:) Olfactory receptor 2A12; (3946:)Olfactory receptor 2A14 (OST182); (3947:) Olfactory receptor 2A2(Olfactory receptor OR7-11); (3948:) Olfactory receptor 2A4 (Olfactoryreceptor OR6-37); (3949:) Olfactory receptor 2A42; (3950:) Olfactoryreceptor 2A5 (Olfactory receptor 7-138/7-141) (OR7-138) (OR7-141);(3951:) Olfactory receptor 2A7; (3952:) Olfactory receptor 2AE1; (3953:)Olfactory receptor 2AG1 (HT3); (3954:) Olfactory receptor 2AJ1; (3955:)Olfactory receptor 2AK2 (Olfactory receptor OR1-47); (3956:) Olfactoryreceptor 2AP1 (Olfactory receptor OR12-9); (3957:) Olfactory receptor2B11; (3958:) Olfactory receptor 2B2 (Olfactory receptor 6-1) (OR6-1)(Hs6M1-10); (3959:) Olfactory receptor 2B3 (Olfactory receptor 6-4)(OR6-4) (Olfactory receptor OR6-14) (Hs6M1-1); (3960:) Olfactoryreceptor 2B6 (Olfactory receptor 6-31) (OR6-31) (Olfactory receptor5-40) (OR5-40) (Hs6M1-32); (3961:) Olfactory receptor 2B8 (Hs6M1-29P);(3962:) Olfactory receptor 2C1 (OLFmf3); (3963:) Olfactory receptor 2C3;(3964:) Olfactory receptor 2D2 (Olfactory receptor 11-610) (OR11-610)(HB2) (Olfactory receptor OR11-88); (3965:) Olfactory receptor 2D3;(3966:) Olfactory receptor 2F1 (Olfactory receptor-like protein OLF3);(3967:) Olfactory receptor 2F2 (Olfactory receptor 7-1) (OR7-1)(Olfactory receptor OR7-6); (3968:) Olfactory receptor 2G2 (Olfactoryreceptor OR1-32); (3969:) Olfactory receptor 2G3 (Olfactory receptorOR1-33); (3970:) Olfactory receptor 2G6; (3971:) Olfactory receptor 2H1(Hs6M1-16) (Olfactory receptor 6-2) (OR6-2) (OLFR42A-9004.14/9026.2);(3972:) Olfactory receptor 2H2 (Hs6M1-12) (Olfactory receptor-likeprotein FAT11); (3973:) Olfactory receptor 2H7 (OLFR42B-9079.6); (3974:)Olfactory receptor 211; (3975:) Olfactory receptor 2J1 (Olfactoryreceptor 6-5) (OR6-5) (Hs6M1-4); (3976:) Olfactory receptor 2J2(Olfactory receptor 6-8) (OR6-8) (Hs6M1-6); (3977:) Olfactory receptor2J3 (Olfactory receptor 6-6) (OR6-6) (Hs6M1-3); (3978:) Olfactoryreceptor 2K2(HTPCRH06); (3979:) Olfactory receptor 2L13; (3980:)Olfactory receptor 2L2 (HTPCRH07); (3981:) Olfactory receptor 2L3;(3982:) Olfactory receptor 2L5 (Olfactory receptor OR1-53); (3983:)Olfactory receptor 2L8 (Olfactory receptor OR1-46); (3984:) Olfactoryreceptor 2M1 (Olfactory receptor-like protein JCG10) (OST037); (3985:)Olfactory receptor 2M2 (OST423); (3986:) Olfactory receptor 2M3(Olfactory receptor OR1-54); (3987:) Olfactory receptor 2M4 (Olfactoryreceptor TPCR100) (OST710) (HTPCRX18) (Olfactory receptor OR1-55);(3988:) Olfactory receptor 2M7 (Olfactory receptor OR1-58); (3989:)Olfactory receptor 2S2 (Olfactory receptor OR9-3); (3990:) Olfactoryreceptor 2T1 (Olfactory receptor 1-25) (OR1-25) (Olfactory receptorOR1-61); (3991:) Olfactory receptor 2T10 (Olfactory receptor OR1-64);(3992:) Olfactory receptor 2T11 (Olfactory receptor OR1-65); (3993:)Olfactory receptor 2T12 (Olfactory receptor OR1-57); (3994:) Olfactoryreceptor 2T2 (Olfactory receptor OR1-43); (3995:) Olfactory receptor2T27 (Olfactory receptor OR1-67); (3996:) Olfactory receptor 2T29;(3997:) Olfactory receptor 2T3; (3998:) Olfactory receptor 2T33(Olfactory receptor OR1-56); (3999:) Olfactory receptor 2T34 (Olfactoryreceptor OR1-63); (4000:) Olfactory receptor 2T35 (Olfactory receptorOR1-66); (4001:) Olfactory receptor 2T4 (Olfactory receptor OR1-60);(4002:) Olfactory receptor 2T5 (Olfactory receptor OR1-62); (4003:)Olfactory receptor 2T6 (OST703); (4004:) Olfactory receptor 2V2(Olfactory receptor OR5-3); (4005:) Olfactory receptor 2W1 (Hs6M1-15);(4006:) Olfactory receptor 2W3 (Olfactory receptor OR1-49); (4007:)Olfactory receptor 2Y1 (Olfactory receptor OR5-2); (4008:) Olfactoryreceptor 2Z1 (Olfactory receptor OR19-4); (4009:) Olfactory receptor 3A1(Olfactory receptor 17-40) (OR17-40); (4010:) Olfactory receptor 3A2(Olfactory receptor 17-228) (OR17-228); (4011:) Olfactory receptor 3A3(Olfactory receptor 17-201) (OR17-201); (4012:) Olfactory receptor 3A4(Olfactory receptor 17-24) (OR17-24); (4013:) Olfactory receptor 4A15(Olfactory receptor OR11-118); (4014:) Olfactory receptor 4A16(Olfactory receptor OR11-117); (4015:) Olfactory receptor 4A4 (Olfactoryreceptor OR11-107); (4016:) Olfactory receptor 4A47 (Olfactory receptorOR11-113); (4017:) Olfactory receptor 4A5 (Olfactory receptor OR11-111);(4018:) Olfactory receptor 4B1 (OST208) (Olfactory receptor OR11-106);(4019:) Olfactory receptor 4C11 (Olfactory receptor OR11-136); (4020:)Olfactory receptor 4C12 (Olfactory receptor OR11-259); (4021:) Olfactoryreceptor 4C13 (Olfactory receptor OR11-260); (4022:) Olfactory receptor4C15 (Olfactory receptor OR11-127) (Olfactory receptor OR11-134);(4023:) Olfactory receptor 4C16 (Olfactory receptor OR11-135); (4024:)Olfactory receptor 4C3 (Olfactory receptor OR11-98); (4025:) Olfactoryreceptor 4C5 (Olfactory receptor OR11-99); (4026:) Olfactory receptor4C6 (Olfactory receptor OR11-138); (4027:) Olfactory receptor 4D1(Olfactory receptor TPCR16); (4028:) Olfactory receptor 4D10 (Olfactoryreceptor OR11-251); (4029:) Olfactory receptor 4D11; (4030:) Olfactoryreceptor 4D2 (Olfactory receptor OR17-24) (B-lymphocyte membrane proteinBC2009); (4031:) Olfactory receptor 4D5 (Olfactory receptor OR11-276);(4032:) Olfactory receptor 4D6 (Olfactory receptor OR11-250); (4033:)Olfactory receptor 4D9 (Olfactory receptor OR11-253); (4034:) Olfactoryreceptor 4E2 (Olfactory receptor OR14-42); (4035:) Olfactory receptor4F14; (4036:) Olfactory receptor 4F15; (4037:) Olfactory receptor 4F17;(4038:) Olfactory receptor 4F29 (Olfactory receptor OR1-1); (4039:)Olfactory receptor 4F3; (4040:) Olfactory receptor 4F4 (HS14a-1-A)(Olfactory receptor OR19-3); (4041:) Olfactory receptor 4F5; (4042:)Olfactory receptor 4F6; (4043:) Olfactory receptor 4H12; (4044:)Olfactory receptor 4K1; (4045:) Olfactory receptor 4K13 (Olfactoryreceptor OR14-27); (4046:) Olfactory receptor 4K14 (Olfactory receptorOR14-22); (4047:) Olfactory receptor 4K15; (4048:) Olfactory receptor4K17; (4049:) Olfactory receptor 4K2; (4050:) Olfactory receptor 4K3;(4051:) Olfactory receptor 4K5; (4052:) Olfactory receptor 4L1(Olfactory receptor OR14-28); (4053:) Olfactory receptor 4M1; (4054:)Olfactory receptor 4M2; (4055:) Olfactory receptor 4N2 (Olfactoryreceptor OR14-8); (4056:) Olfactory receptor 4N4; (4057:) Olfactoryreceptor 4N5 (Olfactory receptor OR14-33); (4058:) Olfactory receptor4P4; (4059:) Olfactory receptor 4Q3 (Olfactory receptor OR14-3); (4060:)Olfactory receptor 4S1; (4061:) Olfactory receptor 4S2; (4062:)Olfactory receptor 4×1; (4063:) Olfactory receptor 4X2; (4064:)Olfactory receptor 51A2; (4065:) Olfactory receptor 51A4; (4066:)Olfactory receptor 51A7; (4067:) Olfactory receptor 51B2 (Odorantreceptor HOR5′beta3); (4068:) Olfactory receptor 51B4 (Odorant receptorHOR5′beta1); (4069:) Olfactory receptor 51B5 (Odorant receptorHOR5′beta5) (Olfactory receptor OR11-37); (4070:) Olfactory receptor51B5 (Odorant receptor HOR5′beta6); (4071:) Olfactory receptor 51D1(Olfactory receptor OR11-14); (4072:) Olfactory receptor 51 E1; (4073:)Olfactory receptor 51 E2 (Prostate-specific G-protein coupled receptor)(HPRAJ); (4074:) Olfactory receptor 51F2; (4075:) Olfactory receptor 51G1; (4076:) Olfactory receptor 51G2; (4077:) Olfactory receptor 51H1;(4078:) Olfactory receptor 51I1 (Odorant receptor HOR5′beta11)(Olfactory receptor OR11-39); (4079:) Olfactory receptor 5112 (Odorantreceptor HOR5′beta12) (Olfactory receptor OR11-38); (4080:) Olfactoryreceptor 51L1; (4081:) Olfactory receptor 51M1 (Odorant receptorHOR5′beta7) (Olfactory receptor OR11-40); (4082:) Olfactory receptor51Q1; (4083:) Olfactory receptor 51 S1; (4084:) Olfactory receptor 51T1;(4085:) Olfactory receptor 51V1 (Odorant receptor HOR3′beta1) (Olfactoryreceptor OR11-36); (4086:) Olfactory receptor 52A1 (HPFH10R) (Odorantreceptor HOR3′beta4); (4087:) Olfactory receptor 52A5 (Odorant receptorHOR3′beta5) (Olfactory receptor OR11-33); (4088:) Olfactory receptor52B2; (4089:) Olfactory receptor 52B4 (Olfactory receptor OR11-3);(4090:) Olfactory receptor 52B6; (4091:) Olfactory receptor 52D1(Odorant receptor HOR5′beta14) (Olfactory receptor OR11-43); (4092:)Olfactory receptor 52E1; (4093:) Olfactory receptor 52E2; (4094:)Olfactory receptor 52E4; (4095:) Olfactory receptor 52E5; (4096:)Olfactory receptor 52E6; (4097:) Olfactory receptor 52E8 (Olfactoryreceptor OR11-54); (4098:) Olfactory receptor 52H1; (4099:) Olfactoryreceptor 5211; (4100:) Olfactory receptor 5212; (4101:) Olfactoryreceptor 52J3; (4102:) Olfactory receptor 52K1; (4103:) Olfactoryreceptor 52K2; (4104:) Olfactory receptor 52L1; (4105:) Olfactoryreceptor 52L2; (4106:) Olfactory receptor 52M1 (Olfactory receptorOR11-11); (4107:) Olfactory receptor 52N1; (4108:) Olfactory receptor52N2; (4109:) Olfactory receptor 52N4; (4110:) Olfactory receptor 52N5;(4111:) Olfactory receptor 52P1; (4112:) Olfactory receptor 52R1;(4113:) Olfactory receptor 52W1 (Olfactory receptor OR11-71); (4114:)Olfactory receptor 56A1; (4115:) Olfactory receptor 56A3; (4116:)Olfactory receptor 56A4; (4117:) Olfactory receptor 56B1 (Olfactoryreceptor OR11-65); (4118:) Olfactory receptor 56B2; (4119:) Olfactoryreceptor 56B4; (4120:) Olfactory receptor 5A1 (OST181); (4121:)Olfactory receptor 5A2; (4122:) Olfactory receptor 5AC2 (HSA1); (4123:)Olfactory receptor 5AK2; (4124:) Olfactory receptor 5AK3; (4125:)Olfactory receptor 5AN1 (Olfactory receptor OR11-244); (4126:) Olfactoryreceptor 5AP2; (4127:) Olfactory receptor 5AR1; (4128:) Olfactoryreceptor 5AS1; (4129:) Olfactory receptor 5AT1; (4130:) Olfactoryreceptor 5AU1; (4131:) Olfactory receptor 5AV1; (4132:) Olfactoryreceptor 5AY1; (4133:) Olfactory receptor 5B12 (Olfactory receptorOR11-241); (4134:) Olfactory receptor 5B117 (Olfactory receptorOR11-237); (4135:) Olfactory receptor 5B2 (OST073) (Olfactory receptorOR11-240); (4136:) Olfactory receptor 5B3 (Olfactory receptor OR11-239);(4137:) Olfactory receptor 5BF1; (4138:) Olfactory receptor 5C1(Olfactory receptor 9-F) (OR9-F); (4139:) Olfactory receptor 5D13;(4140:) Olfactory receptor 5D14; (4141:) Olfactory receptor 5D16;(4142:) Olfactory receptor 5D18; (4143:) Olfactory receptor 5F1(Olfactory receptor 11-10) (OR11-10); (4144:) Olfactory receptor 5H2;(4145:) Olfactory receptor 5H6; (4146:) Olfactory receptor 511(Olfactory receptor-like protein OLF1) (Olfactory receptor OR11-159);(4147:) Olfactory receptor 5J2 (Olfactory receptor OR11-266); (4148:)Olfactory receptor 5K1 (HTPCRX10); (4149:) Olfactory receptor 5K2(Olfactory receptor OR3-9); (4150:) Olfactory receptor 5L1 (OST262);(4151:) Olfactory receptor 5L2 (HTPCRX16); (4152:) Olfactory receptor5M1 (OST050); (4153:) Olfactory receptor 5M10 (Olfactory receptorOR11-207); (4154:) Olfactory receptor 5M11; (4155:) Olfactory receptor5M3 (Olfactory receptor OR1′-191); (4156:) Olfactory receptor 5M8(Olfactory receptor OR11-194); (4157:) Olfactory receptor 5M9 (Olfactoryreceptor OR11-190); (4158:) Olfactory receptor 5P2 (Olfactoryreceptor-like protein JCG3); (4159:) Olfactory receptor 5P3 (Olfactoryreceptor-like protein JCG1); (4160:) Olfactory receptor 5R1 (Olfactoryreceptor OR11-185); (4161:) Olfactory receptor 5T1 (Olfactory receptorOR11-179); (4162:) Olfactory receptor 5T2; (4163:) Olfactory receptor5T3; (4164:) Olfactory receptor 5U1 (Olfactory receptor OR6-25)(Hs6M1-28); (4165:) Olfactory receptor 5V1 (Hs6M1-21); (4166:) Olfactoryreceptor 5W2 (Olfactory receptor OR11-1S55); (4167:) Olfactory receptor6A2 (Olfactory receptor 11-55) (OR11-55) (hP2olfactory receptor);(4168:) Olfactory receptor 6B1 (Olfactory receptor 7-3) (OR7-3); (4169:)Olfactory receptor 6B2 (Olfactory receptor OR2-1); (4170:) Olfactoryreceptor 6B3 (Olfactory receptor OR2-2); (4171:) Olfactory receptor 6C1(OST267); (4172:) Olfactory receptor 6C2 (HSA3); (4173:) Olfactoryreceptor 6C3 (HSA8); (4174:) Olfactory receptor 6C4; (4175:) Olfactoryreceptor 6F1 (Olfactory receptor OR1-38); (4176:) Olfactory receptor6J1; (4177:) Olfactory receptor 6K2; (4178:) Olfactory receptor 6K3;(4179:) Olfactory receptor 6K6; (4180:) Olfactory receptor 6M1(Olfactory receptor OR11-271); (4181:) Olfactory receptor 6N1; (4182:)Olfactory receptor 6N2; (4183:) Olfactory receptor 6P1 (Olfactoryreceptor OR1-12); (4184:) Olfactory receptor 6Q1; (4185:) Olfactoryreceptor 6S1; (4186:) Olfactory receptor 6T1; (4187:) Olfactory receptor6V1; (4188:) Olfactory receptor 6W1 (Olfactory receptor sdolf); (4189:)Olfactory receptor 6×1 (Olfactory receptor OR11-270); (4190:) Olfactoryreceptor 6Y1 (Olfactory receptor OR-11); (4191:) Olfactory receptor 7A10(OST027) (Olfactory receptor OR19-18); (4192:) Olfactory receptor 7A17;(4193:) Olfactory receptor 7A2; (4194:) Olfactory receptor 7A5(Olfactory receptor TPCR92); (4195:) Olfactory receptor 7C1 (Olfactoryreceptor TPCR86); (4196:) Olfactory receptor 7C2 (Olfactory receptor19-18) (OR19-18); (4197:) Olfactory receptor 7D2 (Olfactory receptor19-4) (OR19-4) (HTPCRH03); (4198:) Olfactory receptor 7D4 (Olfactoryreceptor OR19-7); (4199:) Olfactory receptor 7G1 (Olfactory receptor19-15) (OR19-15); (4200:) Olfactory receptor 7G2 (Olfactory receptor19-13) (OR19-13) (oST260); (4201:) Olfactory receptor 7G3 (OST085);(4202:) Olfactory receptor 8A1 (OST025); (4203:) Olfactory receptor 8B12(Olfactory receptor OR11-317); (4204:) Olfactory receptor 8B2; (4205:)Olfactory receptor 8B3; (4206:) Olfactory receptor 8B4; (4207:)Olfactory receptor 8B8 (Olfactory receptor TPCR85) (Olfactory-likereceptor JCG8); (4208:) Olfactory receptor 8D1 (Olfactory receptor-likeprotein JCG9) (OST004) (Olfactory receptor OR11-301); (4209:) Olfactoryreceptor 8D2 (Olfactory receptor-like protein JCG2); (4210:) Olfactoryreceptor 8D4; (4211:) Olfactory receptor 8G1 (Olfactory receptor TPCR25)(Olfactory receptor OR11-281); (4212:) Olfactory receptor 8G2 (Olfactoryreceptor TPCR120) (Olfactory receptor OR11-297); (4213:) Olfactoryreceptor 8G5 (Olfactory receptor OR11-298); (4214:) Olfactory receptor8H1; (4215:) Olfactory receptor 8H2; (4216:) Olfactory receptor 8H3;(4217:) Olfactory receptor 812; (4218:) Olfactory receptor 8J1; (4219:)Olfactory receptor 8J3; (4220:) Olfactory receptor 8K1; (4221:)Olfactory receptor 8K3; (4222:) Olfactory receptor 8K5; (4223:)Olfactory receptor 8S1; (4224:) Olfactory receptor 8U1; (4225:)Olfactory receptor 9A2; (4226:) Olfactory receptor 9A4; (4227:)Olfactory receptor 9G1; (4228:) Olfactory receptor 9G4; (4229:)Olfactory receptor 9G5 (Olfactory receptor OR11-114); (4230:) Olfactoryreceptor 911; (4231:) Olfactory receptor 9K2; (4232:) Olfactory receptor9Q1; (4233:) Olfactory receptor 9Q2; (4234:) olfactory receptor, family4, subfamily F, member 6 [Homo sapiens]; (4235:) oligoadenylatesynthetase; (4236:) O-linked GlcNAc transferase isoform 1 [Homosapiens]; (4237:) O-linked GlcNAc transferase isoform 2 [Homo sapiens];(4238:) Oncomodulin (OM) (Parvalbumin beta); (4239:) Opa-interactingprotein OIP3 [Homo sapiens]; (4240:) Opioid Growth Factor Receptor(OGFr); (4241:) Opioid growth factor receptor (OGFr) (Zeta-type opioidreceptor) (7-60 protein); (4242:) Opioid Receptor; (4243:) opioidreceptor, mu 1 isoform MOR-1 [Homo sapiens]; (4244:) opioid receptor, mu1 isoform MOR-1A [Homo sapiens]; (4245:) opioid receptor, mu 1 isoformMOR-10 [Homo sapiens]; (4246:) opioid receptor, mu 1 isoform MOR-LX[Homo sapiens]; (4247:) Opioid Receptor-Like1 (ORL1) Receptor; (4248:)Opsin-3 (Encephalopsin) (Panopsin); (4249:) Opsin-5 (Neuropsin)(G-protein coupled receptor 136) (G-protein coupled receptor PGR12)(Transmembrane protein 13); (4250:) Orexigenic neuropeptide QRFPreceptor (G-protein coupled receptor103) (SP9155) (AQ27); (4251:) OrexinReceptor; (4252:) Orexin receptor type 1 (Ox1r) (Hypocretin receptortype 1); (4253:) Orexin receptor type 2 (0x2r) (Hypocretin receptor type2); (4254:) Organic Anion Transporter 3 (OAT3); (4255:) Organiccation/carnitine transporter 1 (Solute carrier family 22member 4)(Ergothioneine transporter) (ET transporter); (4256:) ornithineaminotransferase precursor [Homo sapiens]; (4257:) ornithinecarbamoyltransferase precursor [Homo sapiens]; (4258:) Ornithinecarbamoyltransferase, mitochondrial precursor (OTCase) (Ornithinetranscarbamylase); (4259:) Ornithine Decarboxylase; (4260:) ornithinedecarboxylase 1 [Homo sapiens]; (4261:) ornithine decarboxylase-likeprotein [Homo sapiens]; (4262:) Orphan nuclear receptor EAR-2(V-erbA-related protein EAR-2); (4263:) Orphan nuclear receptor NR1D1(V-erbA-related protein EAR-1) (Rev-erbA-alpha); (4264:) Orphan nuclearreceptor NR1D2 (Rev-erb-beta) (EAR-1R) (Orphan nuclear hormone receptorBD73); (4265:) Orphan nuclear receptor NR1I3 (Constitutive androstanereceptor) (CAR) (Constitutive activator of retinoid response)(Constitutive active response) (Orphan nuclear receptor MB67); (4266:)Orphan nuclear receptor NR2E1 (Nuclear receptor TLX) (Tailless homolog)(TII) (hTII); (4267:) Orphan nuclear receptor NR4A1 (Orphan nuclearreceptor HMR) (Early response protein NAK1) (TR3 orphan receptor)(ST-59); (4268:) Orphan nuclear receptor NR4A2 (Orphan nuclear receptorNURR1) (Immediate-early response protein NOT)(Transcriptionally-inducible nuclear receptor); (4269:) Orphan nuclearreceptor NR4A3 (Nuclear hormone receptor NOR-1) (Neuron-derived orphanreceptor 1) (Mitogen-induced nuclear orphan receptor); (4270:) Orphannuclear receptor NR5A2 (Alpha-1-fetoprotein transcription factor)(Hepatocytic transcription factor) (B1-binding factor) (hB1F) (CYP7Apromoter-binding factor) (Liver receptor homolog 1) (LRH-1); (4271:)Orphan nuclear receptor NR6A1 (Germ cell nuclear factor) (GCNF)(Retinoid receptor-related testis-specific receptor) (RTR); (4272:)Orphan nuclear receptor PXR (Pregnane X receptor) (Orphan nuclearreceptor PAR1) (Steroid and xenobiotic receptor) (SXR); (4273:) orphannuclear receptor steroidogenic factor 1, SF-1 (long terminalrepeat-binding protein, ELP) [human, Peptide, 205 aa]; (4274:) Orphannuclear receptor TR2 (Testicular receptor 2); (4275:) Orphan nuclearreceptor TR4 (Orphan nuclear receptor TAK1); (4276:) orphanUDP-glucuronosyltransferase (EC 2.4.-.-)—human; (4277:) OTUdomain-containing protein 7B (Zinc finger protein Cezanne) (Zinc fingerA20 domain-containing protein 1) (Cellular zinc finger anti-NF-kappa Bprotein); (4278:) oxidised low density lipoprotein (lectin-like)receptor 1 [Homo sapiens]; (4279:) Oxidized low-density lipoproteinreceptor 1 (0x-LDL receptor 1) (Lectin-type oxidized LDL receptor 1)(Lectin-like oxidized LDL receptor 1) (Lectin-like ox LDL receptor 1)(LOX-1) (hLOX-1)[Contains:) Oxidized low-density lipoprotein receptor 1,soluble form]; (4280:) Oxidosqualene Cyclase (OSC); (4281:)Oxoeicosanoid receptor 1 (G-protein coupled receptor TG1019) (5-oxo-ETEG-protein coupled receptor) (G-protein coupled receptor170) (G-proteincoupled receptor R527); (4282:) Oxysterols receptor LXR-alpha (Liver Xreceptor alpha) (Nuclear orphan receptor LXR-alpha); (4283:) Oxysterolsreceptor LXR-beta (Liver X receptor beta) (Nuclear orphan receptorLXR-beta) (Ubiquitously-expressed nuclear receptor) (Nuclear receptorNER); (4284:) Oxytocin Receptor (OTR); (4285:) oxytocin-neurophysin Ipreproprotein [Homo sapiens]; (4286:) P/Q-Type Calcium Channel Blocker;(4287:) p136 [Homo sapiens]; (4288:) P2 purinergic Receptor; (4289:)p21-activated kinase 2 [Homo sapiens]; (4290:) P2X purinoceptor 1 (ATPreceptor) (P2X1) (Purinergic receptor); (4291:) P2X purinoceptor 2 (ATPreceptor) (P2×2) (Purinergic receptor); (4292:) P2X purinoceptor 3 (ATPreceptor) (P2×3) (Purinergic receptor); (4293:) P2X purinoceptor 4 (ATPreceptor) (P2×4) (Purinergic receptor); (4294:) P2X purinoceptor 5 (ATPreceptor) (P2×5) (Purinergic receptor); (4295:) P2X purinoceptor 6 (ATPreceptor) (P2×6) (Purinergic receptor) (P2XM) (Purinergic receptorP2X-like 1); (4296:) P2X purinoceptor 7 (ATP receptor) (P2×7)(Purinergic receptor) (P2Z receptor); (4297:) P2X3 Purinergic Receptor;(4298:) P2X7 Purinergic Receptor; (4299:) P2Y purinoceptor 1 (ATPreceptor) (P2Y1) (Purinergic receptor); (4300:) P2Y purinoceptor 11(P2Y11); (4301:) P2Y purinoceptor 12 (P2Y12) (P2Y12 platelet ADPreceptor) (P2Y(ADP)) (ADP-glucose receptor) (ADPG-R) (P2Y(AC))(P2Y(cyc)) (P2T(AC)) (SP1999); (4302:) P2Y purinoceptor 13 (P2Y13)(G-protein coupled receptor 86) (G-protein coupled receptor 94); (4303:)P2Y purinoceptor 14 (P2Y14) (UDP-glucose receptor) (G-protein coupledreceptor 105); (4304:) P2Y purinoceptor 2 (P2Y2) (P2U purinoceptor 1)(P2U1) (ATP receptor) (Purinergic receptor); (4305:) P2Y purinoceptor 4(P2Y4) (Uridine nucleotide receptor) (UNR) (P2P); (4306:) P2Ypurinoceptor 5 (P2Y5) (Purinergic receptor 5) (RB intron encodedG-protein coupled receptor); (4307:) P2Y purinoceptor 6 (P2Y6); (4308:)P2Y purinoceptor 8 (P2Y8); (4309:) P2Y12 Purinergic Receptor; (4310:)P2Y2 Purinergic Receptor; (4311:) p300/CBP-associated factor [Homosapiens]; (4312:) p38 Mitogen-Activated Protein (MAP) Kinase; (4313:)p38 mitogen-activated protein (MAP) kinase activator; (4314:) p53Activator; (4315:) p65 Protein; (4316:) p70 Ribosomal Protein S6 Kinase(S6K); (4317:) p85 beta subunit of phosphatidyl-inositol-3-kinase [Homosapiens]; (4318:) Paired Box Gene 4 (Pax4) Functional; (4319:) Pairedimmunoglobulin-like type 2 receptor alpha precursor (Inhibitory receptorPILR-alpha) (Cell surface receptor FDF03); (4320:) Pairedimmunoglobulin-like type 2 receptor beta precursor (Activating receptorPILR-beta) (Cell surface receptor FDFACT); (4321:) palmitoyl-proteinthioesterase [Homo sapiens]; (4322:) palmitoyl-protein thioesterase 1(ceroid-lipofuscinosis, neuronal1, infantile) [Homo sapiens]; (4323:)Palmitoyl-protein thioesterase 1 precursor (PPT-1) (Palmitoyl-proteinhydrolase 1); (4324:) PAN2 [Homo sapiens]; (4325:) pancreas-enrichedphospholipase C [Homo sapiens]; (4326:) pancreatic ribonucleaseprecursor [Homo sapiens]; (4327:) Pantothenate kinase 1 (Pantothenicacid kinase 1) (hPanK1) (hPanK); (4328:) pantothenate kinase 1 isoformalpha [Homo sapiens]; (4329:) pantothenate kinase 1 isoform beta [Homosapiens]; (4330:) pantothenate kinase 1 isoform gamma [Homo sapiens];(4331:) pantothenate kinase 2 isoform 1 preproprotein [Homo sapiens];(4332:) pantothenate kinase 2 isoform 2 [Homo sapiens]; (4333:)Pantothenate kinase 2, mitochondrial precursor (Pantothenic acid kinase2) (hPANK2); (4334:) Pantothenate kinase 3 (Pantothenic acid kinase 3)(hPanK3); (4335:) pantothenate kinase 3 [Homo sapiens]; (4336:)Pantothenate kinase 4 (Pantothenic acid kinase 4) (hPanK4); (4337:)pantothenate kinase 4 [Homo sapiens]; (4338:) Pappalysin-1 precursor(Pregnancy-associated plasma protein-A) (PAPP-A) (Insulin-like growthfactor-dependent IGF-binding protein4 protease) (IGF-dependent IGFBP-4protease) (IGFBP-4-ase); (4339:) PAPSS1 protein [Homo sapiens]; (4340:)paraoxanase-3 [Homo sapiens]; (4341:) paraoxonase 1 [Homo sapiens];(4342:) paraoxonase 2 isoform 1 [Homo sapiens]; (4343:) paraoxonase 2isoform 2 [Homo sapiens]; (4344:) paraoxonase 3 [Homo sapiens]; (4345:)Parathyroid Hormone (PTH); (4346:) Parathyroid hormone receptorprecursor (PTH2 receptor); (4347:) Parathyroid hormone/parathyroidhormone-related peptide receptor precursor (PTH/PTHr receptor)(PTH/PTHrP type I receptor); (4348:) parkin isoform 1 [Homo sapiens];(4349:) parkin isoform 2 [Homo sapiens]; (4350:) parkin isoform 3 [Homosapiens]; (4351:) PAS domain-containing serine/threonine-protein kinase(PAS-kinase) (PASKIN) (hPASK); (4352:) patatin-like phospholipase domaincontaining 1 isoform 2 [Homo sapiens]; (4353:) patatin-likephospholipase domain containing 1 [Homo sapiens]; (4354:) PCCell-Derived Growth Factor (PCDGF); (4355:) PC1/PC3 [Homo sapiens];(4356:) PC8 precursor; (4357:) PCBD [Homo sapiens]; (4358:) PCK1 [Homosapiens]; (4359:) PCK2 [Homo sapiens]; (4360:) PCTAIRE protein kinase 1[Homo sapiens]; (4361:) PDC-E2 precursor (AA-54 to 561) [Homo sapiens];(4362:) Pepsin; (4363:) Peptide Deformylase (PDF); (4364:) Peptidemethionine sulfoxide reductase (Protein-methionine-5-oxide reductase)(PMSR) (Peptide Met(O) reductase); (4365:)Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (PNGase)(hPNGase) (Peptide:N-glycanase) (N-glycanase 1); (4366:) peptidylarginine deiminase, type IV [Homo sapiens]; (4367:) peptidyl dipeptidaseI [Homo sapiens]; (4368:) peptidylarginine deiminase type III [Homosapiens]; (4369:) peptidylglycine alpha-amidating monooxygenaseCOOH-terminal interactor [Homo sapiens]; (4370:) peptidylglycinealpha-amidating monooxygenase isoform a, preproprotein [Homo sapiens];(4371:) peptidylglycine alpha-amidating monooxygenase isoform b,preproprotein [Homo sapiens]; (4372:) peptidylglycine alpha-amidatingmonooxygenase isoform c, preproprotein [Homo sapiens]; (4373:)peptidylglycine alpha-amidating monooxygenase isoform d, preproprotein[Homo sapiens]; (4374:) “Peptidyl-glycine alpha-amidating monooxygenaseprecursor (PAM)[Includes:) Peptidylglycine alpha-hydroxylatingmonooxygenase (PHM); Peptidyl-alpha-hydroxyglycine alpha-amidating lyase(Peptidylamidoglycolate lyase) (PAL)].”; (4375:) PeptidylprolylCis-Trans Isomerase (PPIase); (4376:) Peptidyl-prolyl cis-transisomerase A (PPIase A) (Rotamase A) (Cyclophilin A) (CyclosporinA-binding protein); (4377:) Peptidyl-prolyl cis-trans isomerase Bprecursor (PPIase) (Rotamase) (Cyclophilin B) (S-cyclophilin) (SCYLP)(CYP-S1); (4378:) Peptidyl-prolyl cis-trans isomerase C (PPIase)(Rotamase) (Cyclophilin C); (4379:) Peptidyl-prolyl cis-trans isomeraseG (Peptidyl-prolyl isomerase G) (PPIase G) (Rotamase G) (Cyclophilin G)(Clk-associating RS-cyclophilin) (CARS-cyclophilin) (CARS-Cyp)(SR-cyclophilin) (SRcyp) (SR-cyp) (CASP10); (4380:) Peptidyl-prolylcis-trans isomerase-like 1 (PPIase) (Rotamase); (4381:) peptidylprolylisomerase A [Homo sapiens]; (4382:) Peptidyl-tRNA hydrolase 2,mitochondrial precursor (PTH 2) (Bcl-2 inhibitor of transcription 1);(4383:) Peripheral Chemoreceptor; (4384:) Peripheral-type benzodiazepinereceptor (PBR) (PKBS) (Mitochondrial benzodiazepine receptor); (4385:)peroxiredoxin 2 isoform a [Homo sapiens]; (4386:) peroxiredoxin 2isoform c [Homo sapiens]; (4387:) peroxiredoxin 5 precursor, isoform a[Homo sapiens]; (4388:) peroxiredoxin 5 precursor, isoform b [Homosapiens]; (4389:) peroxiredoxin 5 precursor, isoform c [Homo sapiens];(4390:) peroxiredoxin 6 [Homo sapiens]; (4391:) Peroxiredoxin-1(Thioredoxin peroxidase 2) (Thioredoxin-dependent peroxide reductase 2)(Proliferation-associated protein PAG) (Natural killer cell-enhancingfactor A) (NKEF-A); (4392:) Peroxiredoxin-2 (Thioredoxin peroxidase 1)(Thioredoxin-dependent peroxide reductase 1) (Thiol-specific antioxidantprotein) (TSA) (PRP) (Natural killer cell-enhancing factor B) (NKEF-B);(4393:) Peroxiredoxin-4 (Prx-IV) (Thioredoxin peroxidase A0372)(Thioredoxin-dependent peroxide reductase A0372) (Antioxidant enzymeAOE372) (AOE37-2); (4394:) Peroxiredoxin-5, mitochondrial precursor(Prx-V) (Peroxisomal antioxidant enzyme) (PLP) (Thioredoxin reductase)(Thioredoxin peroxidase PMP20) (Antioxidant enzyme B166) (AOEB166) (TPxtype VI) (Liver tissue 2D-page spot 71B) (Alu corepressor 1); (4395:)Peroxiredoxin-6 (Antioxidant protein 2) (1-Cys peroxiredoxin) (1-CysPRX) (Acidic calcium-independent phospholipase A2) (aiPLA2)(Non-selenium glutathione peroxidase) (NSGPX) (24 kDa protein) (Liver 2Dpage spot 40) (Red blood cells page spot 12); (4396:) Peroxisomal2,4-dienoyl-CoA reductase (2,4-dienoyl-CoA reductase 2) (pDCR); (4397:)peroxisomal acyl-CoA thioesterase 1 isoform a [Homo sapiens]; (4398:)peroxisomal acyl-CoA thioesterase 1 isoform c [Homo sapiens]; (4399:)“Peroxisomal bifunctional enzyme (PBE) (PBFE) [Includes:) Enoyl-CoAhydratase; 3,2-trans-enoyl-CoA isomerase; 3-hydroxyacyl-CoAdehydrogenase].”; (4400:) Peroxisomal coenzyme A diphosphatase NUDT7(Nucleosidediphosphate-linked moiety X motif 7) (Nudix motif 7); (4401:)peroxisomal D3,D2-enoyl-CoA isomerase isoform 1 [Homo sapiens]; (4402:)peroxisomal D3,D2-enoyl-CoA isomerase isoform 2 [Homo sapiens]; (4403:)peroxisomal enoyl-coenzyme A hydratase-like protein [Homo sapiens];(4404:) Peroxisomal multifunctional enzyme type 2 (MFE-2)(D-bifunctional protein) (DBP) (17-beta-hydroxysteroid dehydrogenase 4)(17-beta-HSD 4) (D-3-hydroxyacyl-CoA dehydratase)(3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholest-24-enoyl-CoAhydratase) (3-hydroxyacyl-CoA dehydrogenase); (4405:) Peroxisomal NADHpyrophosphatase NUDT12 (Nucleosidediphosphate-linked moiety X motif 12)(Nudix motif 12); (4406:) Peroxisomal sarcosine oxidase (PSO)(L-pipecolate oxidase) (L-pipecolic acid oxidase); (4407:) Peroxisomaltrans-2-enoyl-CoA reductase (TERP) (HPDHase) (pVi-ARL) (2,4-dienoyl-CoAreductase-related protein) (DCR-RP); (4408:) peroxisome proliferativeactivated receptor gamma isoform 1 [Homo sapiens]; (4409:) peroxisomeproliferative activated receptor gamma isoform 2 [Homo sapiens]; (4410:)Peroxisome proliferator-activated receptor alpha (PPAR-alpha); (4411:)Peroxisome proliferator-activated receptor delta (PPAR-delta)(PPAR-beta) (Nuclear hormone receptor 1) (NUC1) (NUC1); (4412:)Peroxisome proliferator-activated receptor gamma (PPAR-gamma); (4413:)peroxisome proliferator-activated receptor gamma, coactivator 1 alpha[Homo sapiens]; (4414:) peroxisome proliferator-activated receptorgamma-2—human; (4415:) Peroxisome Proliferator-Activated Receptor-Alpha(PPAR-Alpha); (4416:) Peroxisome Proliferator-Activated Receptor-Delta(PPAR-Delta); (4417:) Peroxisome proliferator-activated receptor-gamma(PPAR-gamma) Partial; (4418:) PFKL protein [Homo sapiens]; (4419:) PFKM[Homo sapiens]; (4420:) PFKM protein [Homo sapiens]; (4421:) PFKPprotein [Homo sapiens]; (4422:) PGK1 [Homo sapiens]; (4423:)P-Glycoprotein (P-gp); (4424:) PH domain leucine-rich repeat-containingprotein phosphatase (PH domain leucine-rich repeat protein phosphatase)(Pleckstrin homology domain-containing family E protein 1)(Suprachiasmatic nucleus circadian oscillatory protein) (hSCOP); (4425:)phenylalanine hydroxylase [Homo sapiens]; (4426:) phenylalaninehydroxylase-stimulating protein, pterin-4-alpha-carbinolaminedehydratase, PHS, PCD [human, liver, Peptide, 103 aa]; (4427:)Phenylalanine-4-hydroxylase (PAH) (Phe-4-monooxygenase); (4428:)Phenylethanolamine N-methyltransferase (PNMTase) (NoradrenalineN-methyltransferase); (4429:) phenylethanolamine N-methyltransferase[Homo sapiens]; (4430:) phenylethanolamine N-methyltransferase; (4431:)phosphate cytidylyltransferase 1, choline, alpha isoform [Homo sapiens];(4432:) phosphatidate cytidylyltransferase 1 [Homo sapiens]; (4433:)phosphatidate cytidylyltransferase 2 [Homo sapiens]; (4434:)phosphatidic acid phosphatase type 2 domain containing 2 [Homo sapiens];(4435:) phosphatidic acid phosphatase type 2A isoform 1 [Homo sapiens];(4436:) phosphatidic acid phosphatase type 2A isoform 2 [Homo sapiens];(4437:) Phosphatidylcholine (PtdCho) Synthesis; (4438:)Phosphatidylcholine:ceramide choline phosphotransferase 1(Transmembraneprotein 23) (Sphingomyelin synthase 1) (Mob protein); (4439:)Phosphatidylcholine:ceramide choline phosphotransferase 2(Sphingomyelinsynthase 2); (4440:) Phosphatidylcholine-sterol acyltransferaseprecursor (Lecithin-cholesterol acyltransferase)(Phospholipid-cholesterol acyltransferase); (4441:)Phosphatidylethanolamine N-methyltransferase (PEAMT) (PEMT) (PEMT2);(4442:) phosphatidylethanolamine N-methyltransferase isoform 1 [Homosapiens]; (4443:) phosphatidylethanolamine N-methyltransferase isoform 2[Homo sapiens]; (4444:) Phosphatidylinositol 3-Kinase (PI3K); (4445:)Phosphatidylinositol 3-kinase catalytic subunit type 3(PtdIns-3-kinasetype 3) (PI3-kinase type 3) (PI3K type 3) (Phosphoinositide-3-kinaseclass 3) (Phosphatidylinositol 3-kinase p100 subunit); (4446:)Phosphatidylinositol 3-kinase regulatory subunit beta (PI3-kinasep85-subunit beta) (PtdIns-3-kinase p85-beta); (4447:)Phosphatidylinositol 4-kinase alpha (P14-kinase alpha) (PtdIns-4-kinasealpha) (PI4K-alpha); (4448:) Phosphatidylinositol 4-kinase beta (PtdIns4-kinase beta) (P14 Kbeta) (PI4K-beta) (NPIK) (PI4K92); (4449:)phosphatidylinositol 4-kinase type II [Homo sapiens]; (4450:)phosphatidylinositol 4-kinase type-II beta [Homo sapiens]; (4451:)phosphatidylinositol 4-kinase, catalytic, alpha polypeptide isoform1[Homo sapiens]; (4452:) phosphatidylinositol 4-kinase, catalytic, alphapolypeptide isoform2 [Homo sapiens]; (4453:) phosphatidylinositol4-kinase, catalytic, beta polypeptide [Homo sapiens]; (4454:)phosphatidylinositol glycan anchor biosynthesis, class K precursor[Homosapiens]; (4455:) phosphatidylinositol glycan anchor biosynthesis, classL [Homo sapiens]; (4456:) phosphatidylinositol glycan anchorbiosynthesis, class P isoform 1 [Homo sapiens]; (4457:)phosphatidylinositol glycan anchor biosynthesis, class P isoform 2 [Homosapiens]; (4458:) phosphatidylinositol glycan anchor biosynthesis, classQ isoform 1 [Homo sapiens]; (4459:) phosphatidylinositol glycan anchorbiosynthesis, class Q isoform 2 [Homo sapiens]; (4460:)phosphatidylinositol glycan anchor biosynthesis, class S [Homo sapiens];(4461:) phosphatidylinositol glycan anchor biosynthesis, class Tprecursor[Homo sapiens]; (4462:) phosphatidylinositol glycan anchorbiosynthesis, class Y isoform 1 [Homo sapiens]; (4463:)phosphatidylinositol glycan anchor biosynthesis, class Y isoform 2 [Homosapiens]; (4464:) phosphatidylinositol glycan class Y [Homo sapiens];(4465:) phosphatidylinositol glycan, class C [Homo sapiens]; (4466:)Phosphatidylinositol N-acetylglucosaminyltransferase subunit A(GlcNAc-PI synthesis protein) (Phosphatidylinositol-glycan biosynthesisclass A protein) (PIG-A); (4467:) phosphatidylinositolN-acetylglucosaminyltransferase subunit A isoform 1 [Homo sapiens];(4468:) phosphatidylinositol N-acetylglucosaminyltransferase subunit Aisoform 3 [Homo sapiens]; (4469:) PhosphatidylinositolN-acetylglucosaminyltransferase subunit P (Phosphatidylinositol-glycanbiosynthesis class P protein) (PIG-P) (Down syndrome critical regionprotein 5) (Down syndrome critical region protein C); (4470:)Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q(Phosphatidylinositol-glycan biosynthesis class Q protein) (PIG-Q)(N-acetylglucosamyl transferase component GPI1); (4471:)Phosphatidylinositol N-acetylglucosaminyltransferase subunit Y(Phosphatidylinositol-glycan biosynthesis class Y protein) (PIG-Y);(4472:) phosphatidylinositol polyphosphate 5-phosphatase isoform a [Homosapiens]; (4473:) phosphatidylinositol polyphosphate 5-phosphataseisoform b [Homo sapiens]; (4474:) Phosphatidylinositol-4,5-bisphosphate3-kinase catalytic subunit gamma isoform (PI3-kinase p110 subunit gamma)(PtdIns-3-kinase subunit p110) (PI3K) (PI3 K gamma) (p120-PI3K); (4475:)Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing betapolypeptide (Phosphoinositide 3-Kinase-C2-beta) (PtdIns-3-kinase C2beta)(PI3K-C2beta) (C2-PI3K); (4476:) Phosphatidylinositol-4-phosphate3-kinase C2 domain-containing alpha polypeptide (Phosphoinositide3-Kinase-C2-alpha) (PtdIns-3-kinase C2 alpha) (PI3K-C2alpha); (4477:)phosphatidylinositol-4-phosphate 5-kinase type 11 alpha [Homo sapiens];(4478:) Phosphatidylinositol-4-phosphate 5-kinase type-1gamma(Phosphatidylinositol-4-phosphate 5-kinase type I gamma)(PtdIns(4)P-5-kinase gamma) (PtdIns PKI gamma) (PIP5KI gamma); (4479:)phosphatidylinositol-4-phosphate 5-kinase, type 1, alpha [Homo sapiens];(4480:) phosphatidylinositol-4-phosphate 5-kinase, type 1, gamma [Homosapiens]; (4481:) Phosphatidylserine Receptor (PTDSR); (4482:)Phosphatidylserine synthase 1 (PtdSer synthase 1) (PSS-1)(Serine-exchange enzyme I); (4483:) Phosphatidylserine synthase 2(PtdSer synthase 2) (PSS-2) (Serine-exchange enzyme 11); (4484:)Phosphodiesterase (PDE); (4485:) phosphodiesterase 5A isoform 1 [Homosapiens]; (4486:) phosphodiesterase 5A isoform 2 [Homo sapiens]; (4487:)phosphodiesterase 5A isoform 3 [Homo sapiens]; (4488:) phosphodiesterase6B, cGMP-specific, rod, beta [Homo sapiens]; (4489:) phosphodiesterase8A isoform 1 [Homo sapiens]; (4490:) phosphodiesterase 8A isoform 2[Homo sapiens]; (4491:) phosphodiesterase 8A isoform 3 [Homo sapiens];(4492:) phosphodiesterase 8A isoform 4 [Homo sapiens]; (4493:)phosphodiesterase II/nucleotide pyrophosphatase beta [Homo sapiens];(4494:) Phosphodiesterase-1 (PDE-1); (4495:) Phosphodiesterase-10A(PDE-10A); (4496:) Phosphodiesterase-2 (PDE-2); (4497:)Phosphodiesterase-3 (PDE-3); (4498:) Phosphodiesterase-4 (PDE-4);(4499:) Phosphodiesterase-5 (PDE-5); (4500:) Phosphodiesterase-5(PDE-5); (4501:) phosphoenolpyruvate carboxykinase (GTP) [Homo sapiens];(4502:) Phosphoenolpyruvate carboxykinase [GTP], mitochondrial precursor(Phosphoenolpyruvate carboxylase) (PEPCK-M); (4503:) Phosphoenolpyruvatecarboxykinase 1 (soluble) [Homo sapiens]; (4504:) Phosphoenolpyruvatecarboxykinase 2 (mitochondrial) [Homo sapiens]; (4505:)Phosphoenolpyruvate carboxykinase, cytosolic [GTP](Phosphoenolpyruvatecarboxylase) (PEPCK-C); (4506:) phosphoenolpyruvate carboxykinase;(4507:) Phosphoethanolamine/phosphocholine phosphatase; (4508:)phosphofructokinase [Homo sapiens]; (4509:) Phosphofructokinase, liver[Homo sapiens]; (4510:) phosphofructokinase, muscle [Homo sapiens];(4511:) phosphofructokinase, platelet [Homo sapiens]; (4512:)phosphofructokinase; (4513:) phosphofructokinase-M; (4514:)phosphofructokinase-P [Homo sapiens]; (4515:) phosphoglucomutase 1 [Homosapiens]; (4516:) Phosphoglucomutase-1 (Glucose phosphomutase 1) (PGM1); (4517:) Phosphoglucomutase-2 (Glucose phosphomutase 2) (PGM 2);(4518:) phosphogluconate dehydrogenase [Homo sapiens]; (4519:)phosphoglycerate dehydrogenase [Homo sapiens]; (4520:) phosphoglyceratekinase [Homo sapiens]; (4521:) Phosphoglycerate kinase 1 (Primerrecognition protein 2) (PRP 2); (4522:) phosphoglycerate kinase 1 [Homosapiens]; (4523:) Phosphoglycerate kinase 2 [Homo sapiens]; (4524:)Phosphoglycerate kinase, testis specific; (4525:) phosphoglyceretekinase 1 [Homo sapiens]; (4526:) phosphoinositide 3-kinase (EC 2.7.-.-)T105—human (fragment); (4527:) phosphoinositide 3-kinase (EC 2.7.-.-)T14-human (fragment); (4528:) Phosphoinositide 3-kinase regulatorysubunit 5 (PI3-kinase regulatory subunit 5) (PI3-kinase p101 subunit)(PtdIns-3-kinase p101) (p101-PI3K)(Phosphatidylinositol-4,5-bisphosphate 3-kinase regulatory subunit)(PtdIns-3-kinase regulatory subunit) (Protein FOAP-2); (4529:)phosphoinositide-3-kinase, catalytic, alpha polypeptide [Homo sapiens];(4530:) phosphoinositide-3-kinase, catalytic, beta polypeptide [Homosapiens]; (4531:) phosphoinositide-3-kinase, catalytic, gammapolypeptide [Homo sapiens]; (4532:) phosphoinositide-3-kinase, class 2,beta polypeptide [Homo sapiens]; (4533:) phosphoinositide-3-kinase,class 3 [Homo sapiens]; (4534:) phosphoinositide-3-kinase, regulatorysubunit 2 (p85 beta) [Homo sapiens]; (4535:) phosphoinositide-3-kinase,regulatory subunit, polypeptide 1 isoform 1 [Homo sapiens]; (4536:)phosphoinositide-3-kinase, regulatory subunit, polypeptide 1 isoform 2[Homo sapiens]; (4537:) phosphoinositide-3-kinase, regulatory subunit,polypeptide 1 isoform 3 [Homo sapiens]; (4538:)phosphoinositide-specific phospholipase C PLC-epsilon [Homo sapiens];(4539:) phospholemman precursor [Homo sapiens]; (4540:) Phospholipase A2(PLA2); (4541:) Phospholipase A2 precursor (Phosphatidylcholine2-acylhydrolase) (Group IB phospholipase A2); (4542:) phospholipase A2,group IIA [Homo sapiens]; (4543:) phospholipase A2, group IIE [Homosapiens]; (4544:) phospholipase A2, group III precursor [Homo sapiens];(4545:) phospholipase A2, group V precursor [Homo sapiens]; (4546:)phospholipase A2, group VI isoform a [Homo sapiens]; (4547:)phospholipase A2, group VI isoform b [Homo sapiens]; (4548:)phospholipase A2, group VII [Homo sapiens]; (4549:) Phospholipase A2,membrane associated precursor (Phosphatidylcholine 2-acylhydrolase)(Group IIA phospholipase A2) (GIIC sPLA2) (Non-pancreatic secretoryphospholipase A2) (NPS-PLA2); (4550:) phospholipase A2; (4551:)phospholipase C delta 3 [Homo sapiens]; (4552:) phospholipase C epsilon[Homo sapiens]; (4553:) phospholipase C epsilon 1 [Homo sapiens];(4554:) phospholipase C gamma 1 isoform a [Homo sapiens]; (4555:)phospholipase C gamma 1 isoform b [Homo sapiens]; (4556:) phospholipaseC, delta 1 [Homo sapiens]; (4557:) phospholipase C, delta 4 [Homosapiens]; (4558:) phospholipase C, epsilon 1 [Homo sapiens]; (4559:)phospholipase C-eta2 [Homo sapiens]; (4560:) Phospholipase D1 (PLD 1)(Choline phosphatase 1) (Phosphatidylcholine-hydrolyzing phospholipaseD1) (hPLD1); (4561:) Phospholipase D2 (PLD 2) (Choline phosphatase 2)(Phosphatidylcholine-hydrolyzing phospholipase D2) (PLD1C) (hPLD2);(4562:) phospholipid scramblase 1 [Homo sapiens]; (4563:) phospholipidtransfer protein isoform a precursor [Homo sapiens]; (4564:)phospholipid transfer protein isoform b precursor [Homo sapiens];(4565:) phospholysine phosphohistidine inorganic pyrophosphatephosphatase (EC 3.6.1.1)—Human; (4566:) phosphomevalonate kinase [Homosapiens]; (4567:) phosphopantetheine adenylyltransferase/dephosphocoenzyme A kinase [Homo sapiens]; (4568:) Phosphopantothenate—cysteineligase (Phosphopantothenoyl cysteine synthetase) (PPC synthetase);(4569:) phosphoprotein phosphatase (EC 3.1.3.16) 2A BR gamma regulatorychain—human; (4570:) phosphoribosyl pyrophosphate amidotransferaseproprotein [Homo sapiens]; (4571:) phosphoribosyl pyrophosphatesynthetase-associated protein 2 [Homo sapiens]; (4572:)phosphoribosylformylglycinamidine synthase [Homo sapiens]; (4573:)phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamidesynthetase, phosphoribosylaminoimidazole synthetase isoform 1 [Homosapiens]; (4574:) phosphoribosylglycinamide formyltransferase,phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazolesynthetase isoform 2 [Homo sapiens]; (4575:) phosphoribosylpyrophosphatesynthetase subunit III; (4576:) Phosphorylase b kinase regulatorysubunit alpha, liver isoform (Phosphorylase kinase alpha L subunit);(4577:) Phosphorylase b kinase regulatory subunit alpha, skeletal muscleisoform (Phosphorylase kinase alpha M subunit); (4578:) Phosphorylase bkinase regulatory subunit beta (Phosphorylase kinase subunit beta);(4579:) phosphorylase kinase gamma subunit 1 [Homo sapiens]; (4580:)phosphorylase kinase, alpha 1 (muscle) [Homo sapiens]; (4581:)phosphoserine aminotransferase isoform 1 [Homo sapiens]; (4582:)phosphoserine aminotransferase isoform 2 [Homo sapiens]; (4583:)Phosphoserine phosphatase (PSP) (O-phosphoserine phosphohydrolase)(PSPase) (L-3-phosphoserine phosphatase); (4584:) phosphoserinephosphatase [Homo sapiens]; (4585:) photoreceptor outer segmentall-trans retinol dehydrogenase [Homo sapiens]; (4586:)Photoreceptor-specific nuclear receptor (Retina-specific nuclearreceptor); (4587:) phytanoil-CoA alpha hydroxylase [Homo sapiens];(4588:) phytanoyl-CoA 2-hydroxylase isoform a precursor [Homo sapiens];(4589:) phytanoyl-CoA 2-hydroxylase isoform b precursor [Homo sapiens];(4590:) Phytanoyl-CoA dioxygenase, peroxisomal precursor (Phytanoyl-CoAalpha-hydroxylase) (PhyH) (Phytanic acid oxidase); (4591:)phytoceramidase, alkaline [Homo sapiens]; (4592:) PI-3 kinase [Homosapiens]; (4593:) PIG50 [Homo sapiens]; (4594:) pim-1 oncogene [Homosapiens]; (4595:) Pim-1 Receptor Tyrosine Kinase; (4596:) PITSLREserine/threonine-protein kinase CDC2L1(Galactosyltransferase-associatedprotein kinase p58/GTA) (Cell division cycle 2-like protein kinase 1)(CLK-1) (CDK11) (p58CLK-1); (4597:) PITSLRE serine/threonine-proteinkinase CDC2L2(Galactosyltransferase-associated protein kinase p58/GTA)(Cell division cycle 2-like protein kinase 2) (CDK11); (4598:) PituitaryAdenylate Cyclase Activating Peptide Receptor 3 (PACAP R3); (4599:)pituitary adenylate cyclase activating peptide receptor type Iprecursor—human; (4600:) Pituitary adenylate cyclase-activatingpolypeptide type I receptor precursor (PACAP type I receptor)(PACAP-R-1); (4601:) PKM2 protein [Homo sapiens]; (4602:) placentacopper monamine oxidase [Homo sapiens]; (4603:) Placental AlkalinePhosphatase (PALP); (4604:) placental alkaline phosphatase preproprotein[Homo sapiens]; (4605:) placental lactogen hormone precursor [Homosapiens]; (4606:) placental lactogen; (4607:) placental-like alkalinephosphatase preproprotein [Homo sapiens]; (4608:) plakoglobin [Homosapiens]; (4609:) plasma carboxypeptidase B2 isoform a preproprotein[Homo sapiens]; (4610:) plasma carboxypeptidase B2 isoform b [Homosapiens]; (4611:) plasma glutathione peroxidase 3 precursor [Homosapiens]; (4612:) plasma kallikrein B1 precursor [Homo sapiens]; (4613:)“Plasma kallikrein precursor (Plasma prekallikrein) (Kininogenin)(Fletcher factor) [Contains:) Plasma kallikrein heavy chain; Plasmakallikrein light chain].”; (4614:) Plasma membrane calcium-transportingATPase 1 (PMCA1) (Plasma membrane calcium pump isoform 1) (Plasmamembrane calcium ATPase isoform 1); (4615:) Plasma membranecalcium-transporting ATPase 2 (PMCA2) (Plasma membrane calcium pumpisoform 2) (Plasma membrane calcium ATPase isoform 2); (4616:) Plasmamembrane calcium-transporting ATPase 3 (PMCA3) (Plasma membrane calciumpump isoform 3) (Plasma membrane calcium ATPase isoform 3); (4617:)Plasma membrane calcium-transporting ATPase 4 (PMCA4) (Plasma membranecalcium pump isoform 4) (Plasma membrane calcium ATPase isoform 4);(4618:) plasminogen [Homo sapiens]; (4619:) Plasminogen activator (PAI);(4620:) Plasminogen activator-1 (PAI-1); (4621:) plasminogen activator,tissue type isoform 1 preproprotein [Homo sapiens]; (4622:) plasminogenactivator, tissue type isoform 2 precursor [Homo sapiens]; (4623:)plasminogen activator, tissue type isoform 3 precursor [Homo sapiens];(4624:) plasminogen activator, urokinase receptor isoform 1 precursor[Homo sapiens]; (4625:) plasminogen activator, urokinase receptorisoform 2 precursor [Homo sapiens]; (4626:) plasminogen activator,urokinase receptor isoform 3 precursor [Homo sapiens]; (4627:)“Plasminogen precursor [Contains:) Plasmin heavy chain A; Activationpeptide; Angiostatin; Plasmin heavy chain A, short form; Plasmin lightchain B].”; (4628:) Plasmodium Falciparum Calcium-Dependent ATPase(PfATP6); (4629:) platelet coagulation factor XI isoform b [Homosapiens]; (4630:) platelet coagulation factor XI precursor [Homosapiens]; (4631:) Platelet Derived Growth Factor Receptor-Alpha(PDGFR-Alpha); (4632:) Platelet Derived Growth Factor Receptor-Beta(PDGFR-Beta); (4633:) platelet factor 4 (chemokine (C-X-C motif) ligand4) [Homo sapiens]; (4634:) Platelet glycoprotein 4 (Plateletglycoprotein IV) (GPIV) (Glycoprotein IIIb) (GPIIIB) (Leukocytedifferentiation antigen CD36) (CD36 antigen) (PAS IV) (PAS-4 protein)(Platelet collagen receptor) (Fatty acid translocase) (FAT)(Thrombospondin receptor); (4635:) Platelet glycoprotein VI precursor;(4636:) Platelet receptor Gi24 precursor; (4637:) Platelet-ActivatingFactor (PAF); (4638:) platelet-activating factor acetylhydrolase 2 [Homosapiens]; (4639:) Platelet-activating factor acetylhydrolase 2,cytoplasmic (Serine-dependent phospholipase A2) (HSD-PLA2); (4640:)Platelet-activating factor acetylhydrolase IB subunit alpha (PAFacetylhydrolase 45 kDa subunit) (PAF-AH 45 kDa subunit) (PAF-AH alpha)(PAFAH alpha) (Lissencephaly-1 protein) (LIS-1); (4641:)Platelet-activating factor acetylhydrolase 1B subunit beta (PAFacetylhydrolase 30 kDa subunit) (PAF-AH 30 kDa subunit) (PAF-AH subunitbeta) (PAFAH subunit beta); (4642:) Platelet-activating factoracetylhydrolase IB subunit gamma (PAF acetylhydrolase 29 kDa subunit)(PAF-AH 29 kDa subunit) (PAF-AH subunit gamma) (PAFAH subunit gamma);(4643:) platelet-activating factor acetylhydrolase, isoform Ib, alphasubunit (45 kD) [Homo sapiens]; (4644:) Platelet-activating factorreceptor (PAF-R); (4645:) Platelet-Derived Growth Factor Receptor(PDGFR); (4646:) platelet-derived growth factor receptor beta precursor[Homo sapiens]; (4647:) Platelet-derived growth factor-D (PDGF-D);(4648:) platelet-type phosphofructokinase [Homo sapiens]; (4649:)Plexin-A3 precursor (Plexin-4) (Semaphorin receptor SEX); (4650:)Plexin-A4 precursor; (4651:) Plexin-B1 precursor (Semaphorin receptorSEP); (4652:) Plexin-B2 precursor (MM1); (4653:) Plexin-B3 precursor;(4654:) Plexin-D1 precursor; (4655:) PMS1 nirs variant 1 [Homo sapiens];(4656:) PMS1 nirs variant 2 [Homo sapiens]; (4657:) PMS1 nirs variant 3[Homo sapiens]; (4658:) PMS1 nirs variant 5 [Homo sapiens]; (4659:) PMS1nirs variant 6 [Homo sapiens]; (4660:) PMS1 nirs variant 7 [Homosapiens]; (4661:) PMS1 nirs variant 8 [Homo sapiens]; (4662:) PMS1 nirsvariant 9 [Homo sapiens]; (4663:) PMS1 postmeiotic segregation increased1 (S. cerevisiae) [Homo sapiens]; (4664:) PMS1 protein [Homo sapiens];(4665:) PMS1 protein homolog 1 (DNA mismatch repair protein PMS1);(4666:) PMS1 protein homolog 2 (DNA mismatch repair protein PMS2);(4667:) PMS2 gene; (4668:) PMS2 postmeiotic segregation increased 2 (S.cerevisiae) [Homo sapiens]; (4669:) PMS2 postmeiotic segregationincreased 2 isoform a [Homo sapiens]; (4670:) PMS2 protein [Homosapiens]; (4671:) PMS2-C terminal-like [Homo sapiens]; (4672:) PMS2CLprotein [Homo sapiens]; (4673:) PMS2L14 [Homo sapiens]; (4674:) PMS2L15[Homo sapiens]; (4675:) PMS2L16 [Homo sapiens]; (4676:) PMS2L5 protein[Homo sapiens]; (4677:) PMS7 [Homo sapiens]; (4678:) Poliovirus receptorprecursor (Nectin-like protein 5) (Necl-5) (CD155 antigen); (4679:)poliovirus receptor-related 4 [Homo sapiens]; (4680:) Poliovirusreceptor-related protein 1 precursor (Herpes virus entry mediator C)(HveC) (Nectin-1) (Herpesvirus Ig-like receptor) (HIgR) (CD111 antigen);(4681:) Poliovirus receptor-related protein 2 precursor (Herpes virusentry mediator B) (HveB) (Nectin-2) (CD112 antigen); (4682:) Polo-LikeKinase (Plk); (4683:) polo-like kinase [Homo sapiens]; (4684:) Polo-LikeKinase 1 (Plk1); (4685:) POLS protein [Homo sapiens]; (4686:) poly(ADP-ribose) glycohydrolase [Homo sapiens]; (4687:) poly (ADP-ribose)polymerase family, member 1 [Homo sapiens]; (4688:) poly (ADP-ribose)polymerase family, member 10 [Homo sapiens]; (4689:) Poly [ADP-ribose]polymerase 1 (PARP-1) (ADPRT) (NAD(+)ADP-ribosyltransferase 1)(Poly[ADP-ribose] synthetase 1); (4690:) Poly(A) polymerase gamma (PAPgamma) (Polynucleotide adenylyl transferase gamma) (SRP RNA 3′adenylating enzyme) (Neo-poly(A) polymerase) (Neo-PAP); (4691:) poly(A)polymerase gamma [Homo sapiens]; (4692:) Poly(A)-specific ribonucleasePARN (Polyadenylate-specific ribonuclease) (Deadenylating nuclease)(Deadenylation nuclease); (4693:) Poly(ADP-Ribose) Glycohydrolase(PARG); (4694:) Poly(ADP-ribose) polymerase (PARP); (4695:)Poly(ADP-ribose) polymerase-1 (PARP-1); (4696:) Poly(ADP-ribose)polymerase-2 (PARP-2); (4697:) poly(rC) binding protein 1 [Homosapiens]; (4698:) polyamine oxidase isoform 1 [Homo sapiens]; (4699:)polyamine oxidase isoform 2 [Homo sapiens]; (4700:) polyamine oxidaseisoform 3 [Homo sapiens]; (4701:) polyamine oxidase isoform 4 [Homosapiens]; (4702:) Polycystic kidney and hepatic disease 1 precursor(Fibrocystin) (Polyductin) (Tigmin); (4703:) polymerase (DNA directed)kappa [Homo sapiens]; (4704:) polymerase (DNA directed), beta [Homosapiens]; (4705:) polymerase (DNA directed), delta 2, regulatory subunit[Homo sapiens]; (4706:) polymerase (DNA directed), eta [Homo sapiens];(4707:) polymerase (DNA directed), gamma 2, accessory subunit [Homosapiens]; (4708:) polymerase (DNA directed), lambda [Homo sapiens];(4709:) polymerase (DNA-directed), alpha [Homo sapiens]; (4710:)polymerase (RNA) III (DNA directed) polypeptide A, 155 kDa [Homosapiens]; (4711:) polymerase (RNA) III (DNA directed) polypeptide C (62kD) [Homo sapiens]; (4712:) polynucleotide kinase 3′-phosphatase [Homosapiens]; (4713:) Polypeptide N-acetylgalactosaminyltransferase 1(Protein-UDPacetylgalactosaminyltransferase 1) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 1) (Polypeptide GalNActransferase 1)(GalNAc-T1) (pp-GaNTase 1) [Contains:) PolypeptideN-acetylgalactosaminyltransferase 1 soluble form]; (4714:) PolypeptideN-acetylgalactosaminyltransferase 10(Protein-UDPacetylgalactosaminyltransferase 10) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 10) (Polypeptide GalNActransferase 10)(GalNAc-T10) (pp-GaNTase 10); (4715:) PolypeptideN-acetylgalactosaminyltransferase 11(Protein-UDPacetylgalactosaminyltransferase 11) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 11) (Polypeptide GalNActransferase 11)(GalNAc-T11) (pp-GaNTase 11); (4716:) PolypeptideN-acetylgalactosaminyltransferase 12(Protein-UDPacetylgalactosaminyltransferase 12) (UDP-GalNAc: polypeptideN-acetylgalactosaminyltransferase 12) (Polypeptide GalNActransferase 12)(GalNAc-T12) (pp-GaNTase 12); (4717:) PolypeptideN-acetylgalactosaminyltransferase 13(Protein-UDPacetylgalactosaminyltransferase 13) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 13) (Polypeptide GalNActransferase 13)(GalNAc-T13) (pp-GaNTase 13); (4718:) PolypeptideN-acetylgalactosaminyltransferase 14(Protein-UDPacetylgalactosaminyltransferase 14) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 14) (Polypeptide GalNActransferase 14)(GalNAc-T14) (pp-GaNTase 14); (4719:) PolypeptideN-acetylgalactosaminyltransferase 2(Protein-UDPacetylgalactosaminyltransferase 2) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 2) (Polypeptide GalNActransferase 2)(GalNAc-T2) (pp-GaNTase 2) [Contains:) PolypeptideN-acetylgalactosaminyltransferase 2 soluble form]; (4720:) polypeptideN-acetylgalactosaminyltransferase 2 [Homo sapiens]; (4721:) PolypeptideN-acetylgalactosaminyltransferase 3(Protein-UDPacetylgalactosaminyltransferase 3) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 3) (Polypeptide GalNActransferase 3)(GalNAc-T3) (pp-GaNTase 3); (4722:) PolypeptideN-acetylgalactosaminyltransferase 4(Protein-UDPacetylgalactosaminyltransferase 4) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 4) (Polypeptide GalNActransferase 4)(GalNAc-T4) (pp-GaNTase 4); (4723:) PolypeptideN-acetylgalactosaminyltransferase 6(Protein-UDPacetylgalactosaminyltransferase 6) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 6) (Polypeptide GalNActransferase 6)(GalNAc-T6) (pp-GaNTase 6); (4724:) polypeptideN-acetylgalactosaminyltransferase 7 [Homo sapiens]; (4725:) polypeptideN-acetylgalactosaminyltransferase 8 [Homo sapiens]; (4726:) PolypeptideN-acetylgalactosaminyltransferase 9(Protein-UDPacetylgalactosaminyltransferase 9) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase 9) (Polypeptide GalNActransferase 9)(GalNAc-T9) (pp-GaNTase 9); (4727:) PolypeptideN-acetylgalactosaminyltransferase-like protein 2(Protein-UDPacetylgalactosaminyltransferase-like protein 2) (UDP-GalNAc:polypeptideN-acetylgalactosaminyltransferase-like protein 2) (Polypeptide GalNActransferase-like protein 2) (GalNAc-T-like protein 2) (pp-GaNTase-likeprotein 2); (4728:) polyserase-2 [Homo sapiens]; (4729:) Polyserase-2precursor (Polyserine protease 2) (Protease serine-36); (4730:) Porcineendogenous retrovirus A receptor 1 precursor (PERV-A receptor 1)(Protein GPR172A); (4731:) Porcine endogenous retrovirus A receptor 2precursor (PERV-A receptor 2) (Protein GPR172B); (4732:) Poriminprecursor (Transmembrane protein 123) (Pro-oncosis receptor inducingmembrane injury) (Keratinocytes-associated transmembrane protein 3)(KCT-3); (4733:) Porphobilinogen deaminase (Hydroxymethylbilanesynthase) (HMBS) (Pre-uroporphyrinogen synthase) (PBG-D); (4734:)“porphobilinogen deaminase; PBGD [Homo sapiens].”; (4735:) postmeioticsegregation 1 [Homo sapiens]; (4736:) postmeiotic segregation increased2 nirs variant 2 [Homo sapiens]; (4737:) postmeiotic segregationincreased 2 nirs variant 5 [Homo sapiens]; (4738:) postmeioticsegregation increased 2-like 5 [Homo sapiens]; (4739:) postreplicationrepair protein hRAD18p [Homo sapiens]; (4740:) PP3895 [Homo sapiens];(4741:) PPP2R5E protein [Homo sapiens]; (4742:) prenyl diphosphatesynthase, subunit 1 [Homo sapiens]; (4743:) prenyl protein peptidaseRCE1 isoform 1 [Homo sapiens]; (4744:) prenyl protein peptidase RCE1isoform 2 [Homo sapiens]; (4745:) prenylcysteine lyase [Homo sapiens];(4746:) prenylcysteine oxidase 1 [Homo sapiens]; (4747:) presenilin 1[Homo sapiens]; (4748:) presenilin 2 isoform 1 [Homo sapiens]; (4749:)presenilin 2 isoform 2 [Homo sapiens]; (4750:) “Presenilin-1 (PS-1)(Protein S182) [Contains:) Presenilin-1 NTF subunit; Presenilin-1 CTFsubunit; Presenilin-1 CTF12 (PSI-CTF12)].”; (4751:) Presequenceprotease, mitochondrial precursor (hPreP)(Pitrilysinmetalloproteinase 1) (Metalloprotease 1) (hMP1); (4752:)Presqualene diphosphate phosphatase (Phosphatidic acid phosphatase type2 domain-containing protein 2); (4753:) prion protein preproprotein[Homo sapiens]; (4754:) pristanoyl-CoA oxidase [Homo sapiens]; (4755:)Pro oligopeptidase; (4756:) Probable allantoicase (Allantoateamidinohydrolase); (4757:) Probable C->U-editing enzyme APOBEC-2;(4758:) Probable calcium-transporting ATPase KIAA0703; (4759:) ProbableDNA dC->dU-editing enzyme APOBEC-3A (Phorbolin-1); (4760:) Probable DNAdC->dU-editing enzyme APOBEC-3B (Phorbolin-1-related protein)(Phorbolin-2/3); (4761:) Probable DNA dC->dU-editing enzyme APOBEC-3C(APOBEC1-like) (Phorbolin I protein); (4762:) Probable DNAdC->dU-editing enzyme APOBEC-3D; (4763:) Probable E3 ubiquitin-proteinligase HECTD2 (HECT domain-containing protein 2); (4764:) Probable E3ubiquitin-protein ligase HECTD3 (HECT domain-containing protein 3);(4765:) Probable G-protein coupled receptor 1; (4766:) ProbableG-protein coupled receptor 101; (4767:) Probable G-protein coupledreceptor 110 precursor (G-protein coupled receptor PGR19) (G-proteincoupled receptor KPG_(—)012); (4768:) Probable G-protein coupledreceptor 111 (G-protein coupled receptor PGR20); (4769:) ProbableG-protein coupled receptor 112; (4770:) Probable G-protein coupledreceptor 113 precursor (G-protein coupled receptor PGR23); (4771:)Probable G-protein coupled receptor 114 precursor (G-protein coupledreceptor PGR27); (4772:) Probable G-protein coupled receptor 115(G-protein coupled receptor PGR18); (4773:) Probable G-protein coupledreceptor 116 precursor; (4774:) Probable G-protein coupled receptor 119;(4775:) Probable G-protein coupled receptor 12; (4776:) ProbableG-protein coupled receptor 123; (4777:) Probable G-protein coupledreceptor 124 precursor (Tumor endothelial marker 5); (4778:) ProbableG-protein coupled receptor 125 precursor; (4779:) Probable G-proteincoupled receptor 126 precursor; (4780:) Probable G-protein coupledreceptor 128 precursor; (4781:) Probable G-protein coupled receptor 132(G2 accumulation protein); (4782:) Probable G-protein coupled receptor133 precursor (G-protein coupled receptor PGR25); (4783:) ProbableG-protein coupled receptor 135; (4784:) Probable G-protein coupledreceptor 139 (G(q)-coupled orphan receptor GPRg1) (G-protein-coupledreceptor PGR3); (4785:) Probable G-protein coupled receptor 141(G-protein coupled receptor PGR13); (4786:) Probable G-protein coupledreceptor 142 (G-protein coupled receptor PGR2); (4787:) ProbableG-protein coupled receptor 144 (G-protein coupled receptor PGR24);(4788:) Probable G-protein coupled receptor 148 (G-protein coupledreceptor PGR6) (Brain and testis restricted GPCR); (4789:) ProbableG-protein coupled receptor 149 (G-protein coupled receptor PGR10);(4790:) Probable G-protein coupled receptor 150; (4791:) ProbableG-protein coupled receptor 151 (G-protein coupled receptor PGR7)(GPCR-2037); (4792:) Probable G-protein coupled receptor 152 (G-proteincoupled receptor PGR5); (4793:) Probable G-protein coupled receptor 153(G-protein coupled receptor PGR1); (4794:) Probable G-protein coupledreceptor 156 (GABAB-related G-protein coupled receptor) (G-proteincoupled receptor PGR28); (4795:) Probable G-protein coupled receptor157; (4796:) Probable G-protein coupled receptor 158 precursor; (4797:)Probable G-protein coupled receptor 160; (4798:) Probable G-proteincoupled receptor 161 (G-protein coupled receptor RE2); (4799:) ProbableG-protein coupled receptor 162 (Gene-rich cluster gene Aprotein);(4800:) Probable G-protein coupled receptor 171 (G-protein coupledreceptor H963); (4801:) Probable G-protein coupled receptor 173 (Superconserved receptor expressed in brain 3); (4802:) Probable G-proteincoupled receptor 174; (4803:) Probable G-protein coupled receptor 176(HB-954); (4804:) Probable G-protein coupled receptor 179 precursor(Probable G-protein coupled receptor 158-like 1); (4805:) ProbableG-protein coupled receptor 18; (4806:) Probable G-protein coupledreceptor 19 (GPR-NGA); (4807:) Probable G-protein coupled receptor 20;(4808:) Probable G-protein coupled receptor 21; (4809:) ProbableG-protein coupled receptor 22; (4810:) Probable G-protein coupledreceptor 25; (4811:) Probable G-protein coupled receptor 26; (4812:)Probable G-protein coupled receptor 27 (Super conserved receptorexpressed in brain 1); (4813:) Probable G-protein coupled receptor 3(ACCA orphan receptor); (4814:) Probable G-protein coupled receptor 31;(4815:) Probable G-protein coupled receptor 32; (4816:) ProbableG-protein coupled receptor 33; (4817:) Probable G-protein coupledreceptor 34; (4818:) Probable G-protein coupled receptor 35; (4819:)Probable G-protein coupled receptor 37 precursor (Endothelin Breceptor-like protein 1) (ETBR-LP-1) (Parkin-associated endothelinreceptor-like receptor) (PAELR); (4820:) Probable G-protein coupledreceptor 39; (4821:) Probable G-protein coupled receptor 4 (G-proteincoupled receptor 19); (4822:) Probable G-protein coupled receptor 45(PSP24-alpha) (PSP24-1); (4823:) Probable G-protein coupled receptor 52;(4824:) Probable G-protein coupled receptor 55; (4825:) ProbableG-protein coupled receptor 61 (Biogenic amine receptor-like G-proteincoupled receptor); (4826:) Probable G-protein coupled receptor 62(hGPCR8); (4827:) Probable G-protein coupled receptor 63 (PSP24-beta)(PSP24-2); (4828:) Probable G-protein coupled receptor 75; (4829:)Probable G-protein coupled receptor 78; (4830:) Probable G-proteincoupled receptor 81 (G-protein coupled receptor104); (4831:) ProbableG-protein coupled receptor 82; (4832:) Probable G-protein coupledreceptor 83 precursor (G-protein coupled receptor 72); (4833:) ProbableG-protein coupled receptor 84 (Inflammation-related G-protein coupledreceptor EX33); (4834:) Probable G-protein coupled receptor 85 (Superconserved receptor expressed in brain 2); (4835:) Probable G-proteincoupled receptor 87 (G-protein coupled receptor95); (4836:) ProbableG-protein coupled receptor 88 (Striatum-specific G-protein coupledreceptor); (4837:) Probable G-protein coupled receptor 92; (4838:)Probable G-protein coupled receptor 97 precursor (G-protein coupledreceptor PGR26); (4839:) Probable G-protein-coupled receptor 146(G-protein coupled receptor PGR8); (4840:) Probable P2Y purinoceptorGPR17 (G protein-coupled receptor 17) (P2Y-like receptor) (R12); (4841:)Probable ubiquitin carboxyl-terminal hydrolase CYLD(Ubiquitinthioesterase CYLD) (Ubiquitin-specific-processing proteaseCYLD) (Deubiquitinating enzyme CYLD); (4842:) Probable ubiquitincarboxyl-terminal hydrolase FAF-X (Ubiquitinthioesterase FAF-X)(Ubiquitin-specific-processing protease FAF-X) (Deubiquitinating enzymeFAF-X) (Fat facets protein-related, X-linked) (Ubiquitin-specificprotease 9, X chromosome); (4843:) Probable ubiquitin carboxyl-terminalhydrolase FAF-Y (Ubiquitinthioesterase FAF-Y)(Ubiquitin-specific-processing protease FAF-Y) (Deubiquitinating enzymeFAF-Y) (Fat facets protein-related, Y-linked) (Ubiquitin-specificprotease 9, Y chromosome); (4844:) Probable ubiquitin-conjugating enzymeE2 W (Ubiquitin-protein ligase W) (Ubiquitin carrier protein W); (4845:)procaspase-8 [Homo sapiens]; (4846:) procaspase-8L [Homo sapiens];(4847:) procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 isoform aprecursor [Homo sapiens]; (4848:) procollagen-lysine, 2-oxoglutarate5-dioxygenase 2 isoform b precursor [Homo sapiens]; (4849:)procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 precursor [Homosapiens]; (4850:) Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1precursor (Lysylhydroxylase 1) (LH1); (4851:) Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 precursor (Lysylhydroxylase 2) (LH2);(4852:) Progesterone Receptor (PR); (4853:)Progesterone-induced-blocking factor 1; (4854:) Progestin and adipoQreceptor family member 3 (Progestin and adipoQ receptor family memberIII); (4855:) Progestin and adipoQ receptor family member 4 (Progestinand adipoQ receptor family member IV); (4856:) Progestin and adipoQreceptor family member 6 (Progestin and adipoQ receptor family memberVI); (4857:) Progestin and adipoQ receptor family member 9 (Progestinand adipoQ receptor family member IX); (4858:) Programmed Cell Death 1(PDCD1) Receptor; (4859:) Programmed cell death 1 ligand 1 precursor(Programmed death ligand 1) (PD-L1) (PDCD1 ligand 1) (B7 homolog 1)(B7-H1) (CD274 antigen); (4860:) Programmed cell death 1 ligand 2precursor (Programmed death ligand 2) (PD-L2) (PD-1-ligand 2) (PDCD1ligand 2) (Butyrophilin B7-DC) (B7-DC) (CD273 antigen); (4861:)Prohibitin-2 (B-cell receptor-associated protein BAP37) (Repressor ofestrogen receptor activity) (D-prohibitin); (4862:) prohormoneconvertase 2 [Homo sapiens]; (4863:) prohormone convertase 2, PC2[human, Peptide, 638 aa]; (4864:) prohormone convertase; (4865:)proinsulin precursor [Homo sapiens]; (4866:) Prokineticin 2 (PK2)Receptor; (4867:) Prokineticin receptor 1 (PK-R1) (G-protein coupledreceptor 73) (GPR73a) (G-protein coupled receptor ZAQ); (4868:)Prokineticin receptor 2 (PK-R2) (G-protein coupled receptor 73-like1)(GPR73b) (GPRg2); (4869:) Prolactin receptor precursor (PRL-R); (4870:)Prolactin-releasing peptide receptor (PrRP receptor) (PrRPR) (G-proteincoupled receptor 10) (hGR3); (4871:) proliferating cell nuclear antigen[Homo sapiens]; (4872:) Prolyl 4-Hydroxylase; (4873:) prolyl4-hydroxylase alpha (II) subunit [Homo sapiens]; (4874:) Prolyl4-hydroxylase alpha-2 subunit precursor (4-PH alpha-2)(Procollagen-proline, 2-oxoglutarate-4-dioxygenase alpha-2 subunit);(4875:) prolyl 4-hydroxylase, alpha I subunit isoform 1 precursor [Homosapiens]; (4876:) prolyl 4-hydroxylase, alpha I subunit isoform 2precursor [Homo sapiens]; (4877:) prolyl 4-hydroxylase, alpha II subunitisoform 1 precursor [Homo sapiens]; (4878:) prolyl 4-hydroxylase, alphaII subunit isoform 2 precursor [Homo sapiens]; (4879:) prolyl4-hydroxylase, alpha III subunit precursor [Homo sapiens]; (4880:)prolyl 4-hydroxylase, beta subunit [Homo sapiens]; (4881:) ProlylEndopeptidase (PEP); (4882:) prolyl endopeptidase [Homo sapiens];(4883:) prolylcarboxypeptidase isoform 1 preproprotein [Homo sapiens];(4884:) prolylcarboxypeptidase isoform 2 preproprotein [Homo sapiens];(4885:) prolylcarboxypeptidase; (4886:) pro-matrixmetalloproteinase-3—human (fragment); (4887:) proMch6; (4888:)Promyelocytic Leukemia/Retinoic Acid Receptor Alpha (PML/RAR) Protein;(4889:) Properdin precursor (Factor P); (4890:) “propionyl CoAcarboxylase alpha subunit; PCCA [Homo sapiens].”; (4891:) propionylCoenzyme A carboxylase, alpha polypeptide [Homo sapiens]; (4892:)propionyl-CoA carboxylase [Homo sapiens]; (4893:) Propionyl-CoAcarboxylase alpha chain, mitochondrial precursor (PCCase subunit alpha)(Propanoyl-CoA:carbon dioxide ligase subunit alpha); (4894:)propionyl-CoA carboxylase alpha polypeptide precursor [Homo sapiens];(4895:) propionyl-CoA carboxylase alpha subunit [Homo sapiens]; (4896:)Propionyl-CoA carboxylase beta chain, mitochondrial precursor (PCCasesubunit beta) (Propanoyl-CoA:carbon dioxide ligase subunit beta);(4897:) propionyl-CoA carboxylase; (4898:) propionyl-Coenzyme Acarboxylase, alpha polypeptide precursor [Homo sapiens]; (4899:)proprotein convertase subtilisin/kexin type 1 preproprotein [Homosapiens]; (4900:) proprotein convertase subtilisin/kexin type 2 [Homosapiens]; (4901:) proprotein convertase subtilisin/kexin type 5preproprotein [Homo sapiens]; (4902:) Proprotein convertasesubtilisin/kexin type 6 precursor (Paired basic amino acid cleavingenzyme 4) (Subtilisin/kexin-like protease PACE4) (Subtilisin-likeproprotein convertase 4) (SPC4); (4903:) Proprotein convertasesubtilisin/kexin type 7 precursor (Proprotein convertase PC7)(Subtilisin/kexin-like protease PC7) (Prohormone convertase PC7) (PC8)(hPC8) (Lymphoma proprotein convertase); (4904:) proprotein convertasesubtilisin/kexin type 7 preproprotein [Homo sapiens]; (4905:) Proproteinconvertase subtilisin/kexin type 9 precursor (Proprotein convertase PC9)(Subtilisin/kexin-like protease PC9) (Neural apoptosis-regulatedconvertase 1) (NARC-1); (4906:) prosaposin isoform a preproprotein [Homosapiens]; (4907:) prosaposin isoform b preproprotein [Homo sapiens];(4908:) prosaposin isoform c preproprotein [Homo sapiens]; (4909:)Prostacyclin receptor (Prostanoid IP receptor) (PGI receptor)(Prostaglandin I2 receptor); (4910:) Prostaglandin D2 (PGD2) Receptor;(4911:) Prostaglandin D2 receptor (Prostanoid DP receptor) (PGDreceptor); (4912:) Prostaglandin E synthase (Microsomal glutathioneS-transferase 1-like 1) (MGST1-L1) (p53-induced apoptosis protein 12);(4913:) prostaglandin E synthase [Homo sapiens]; (4914:) Prostaglandin Esynthase 2 (Microsomal prostaglandin E synthase 2) (mPGES-2) [Contains:)Prostaglandin E synthase 2 truncated form]; (4915:) Prostaglandin E1(PGE1) Receptor; (4916:) prostaglandin E2 receptor EP3-chain—human;(4917:) Prostaglandin E2 receptor, EP1 subtype (Prostanoid EP1 receptor)(PGE receptor, EP1 subtype); (4918:) Prostaglandin E2 receptor, EP2subtype (Prostanoid EP2 receptor) (PGE receptor, EP2 subtype); (4919:)Prostaglandin E2 receptor, EP3 subtype (Prostanoid EP3 receptor) (PGEreceptor, EP3 subtype) (PGE2-R); (4920:) Prostaglandin E2 receptor, EP4subtype (Prostanoid EP4 receptor) (PGE receptor, EP4 subtype); (4921:)Prostaglandin F2 alpha (PGF2 alpha) Receptor; (4922:) ProstaglandinF2-alpha receptor (Prostanoid FP receptor) (PGF receptor) (PGF2 alphareceptor); (4923:) Prostaglandin G/H synthase 1 precursor(Cyclooxygenase-1) (COX-1) (Prostaglandin-endoperoxide synthase 1)(Prostaglandin H2 synthase 1) (PGH synthase 1) (PGHS-1) (PHS1); (4924:)Prostaglandin G/H synthase 2 precursor (Cyclooxygenase-2) (COX-2)(Prostaglandin-endoperoxide synthase 2) (Prostaglandin H2 synthase 2)(PGH synthase 2) (PGHS-2) (PHS II); (4925:) Prostaglandin I2 (PGI2)Receptor; (4926:) prostaglandin 12 (prostacyclin) synthase [Homosapiens]; (4927:) prostaglandin-D synthase [Homo sapiens]; (4928:)prostaglandin-endoperoxide synthase 1 isoform 1 precursor [Homosapiens]; (4929:) prostaglandin-endoperoxide synthase 1 isoform 2precursor [Homo sapiens]; (4930:) prostaglandin-endoperoxide synthase 2precursor [Homo sapiens]; (4931:) prostaglandin-endoperoxide synthase-1[Homo sapiens]; (4932:) Prostasin; (4933:) prostasin preproprotein [Homosapiens]; (4934:) Prostate-Specific Membrane Antigen (PSMA); (4935:)prostatic acid phosphatase precursor [Homo sapiens]; (4936:) protease,serine, 1 preproprotein [Homo sapiens]; (4937:) protease, serine, 2preproprotein [Homo sapiens]; (4938:) protease, serine, 22 [Homosapiens]; (4939:) protease, serine, 36 [Homo sapiens]; (4940:)Protease-Activated Receptor 1 (PAR1); (4941:) Proteasome; (4942:)proteasome 26S ATPase subunit 1 [Homo sapiens]; (4943:) proteasome 26SATPase subunit 2 [Homo sapiens]; (4944:) proteasome 26S ATPase subunit 3[Homo sapiens]; (4945:) proteasome 26S ATPase subunit 4 isoform 1 [Homosapiens]; (4946:) proteasome 26S ATPase subunit 4 isoform 2 [Homosapiens]; (4947:) proteasome 26S ATPase subunit 5 [Homo sapiens];(4948:) proteasome 26S ATPase subunit 6 [Homo sapiens]; (4949:)proteasome 26S non-ATPase subunit 1 [Homo sapiens]; (4950:) proteasome26S non-ATPase subunit 10 isoform 2 [Homo sapiens]; (4951:) proteasome26S non-ATPase subunit 10 isoform 1 [Homo sapiens]; (4952:) proteasome26S non-ATPase subunit 11 [Homo sapiens]; (4953:) proteasome 26Snon-ATPase subunit 12 [Homo sapiens]; (4954:) proteasome 26S non-ATPasesubunit 13 isoform 1 [Homo sapiens]; (4955:) proteasome 26S non-ATPasesubunit 13 isoform 2 [Homo sapiens]; (4956:) proteasome 26S non-ATPasesubunit 2 [Homo sapiens]; (4957:) proteasome 26S non-ATPase subunit 3[Homo sapiens]; (4958:) proteasome 26S non-ATPase subunit 4 isoform 1[Homo sapiens]; (4959:) proteasome 26S non-ATPase subunit 4 isoform 2[Homo sapiens]; (4960:) proteasome 26S non-ATPase subunit 5 [Homosapiens]; (4961:) proteasome 26S non-ATPase subunit 7 [Homo sapiens];(4962:) proteasome 26S non-ATPase subunit 8 [Homo sapiens]; (4963:)proteasome 26S non-ATPase subunit 9 [Homo sapiens]; (4964:) proteasomeactivator hPA28 subunit beta [Homo sapiens]; (4965:) proteasomeactivator subunit 1 isoform 1 [Homo sapiens]; (4966:) proteasomeactivator subunit 1 isoform 2 [Homo sapiens]; (4967:) proteasomeactivator subunit 2 [Homo sapiens]; (4968:) proteasome activator subunit3 isoform 1 [Homo sapiens]; (4969:) proteasome activator subunit 3isoform 2 [Homo sapiens]; (4970:) proteasome alpha 1 subunit isoform 1[Homo sapiens]; (4971:) proteasome alpha 1 subunit isoform 2 [Homosapiens]; (4972:) proteasome alpha 2 subunit [Homo sapiens]; (4973:)proteasome alpha 3 subunit isoform 1 [Homo sapiens]; (4974:) proteasomealpha 3 subunit isoform 2 [Homo sapiens]; (4975:) proteasome alpha 4subunit [Homo sapiens]; (4976:) proteasome alpha 5 subunit [Homosapiens]; (4977:) proteasome alpha 6 subunit [Homo sapiens]; (4978:)proteasome alpha 7 subunit [Homo sapiens]; (4979:) proteasome beta 1subunit [Homo sapiens]; (4980:) proteasome beta 10 subunit proprotein[Homo sapiens]; (4981:) proteasome beta 2 subunit [Homo sapiens];(4982:) proteasome beta 3 subunit [Homo sapiens]; (4983:) proteasomebeta 4 subunit [Homo sapiens]; (4984:) proteasome beta 5 subunit [Homosapiens]; (4985:) proteasome beta 6 subunit [Homo sapiens]; (4986:)proteasome beta 7 subunit proprotein [Homo sapiens]; (4987:) proteasomebeta 8 subunit isoform E1 proprotein [Homo sapiens]; (4988:) proteasomebeta 8 subunit isoform E2 proprotein [Homo sapiens]; (4989:) proteasomebeta 9 subunit isoform 1 proprotein [Homo sapiens]; (4990:) proteasomebeta 9 subunit isoform 2 proprotein [Homo sapiens]; (4991:) proteasomeinhibitor subunit 1 isoform 1 [Homo sapiens]; (4992:) proteasomeinhibitor subunit 1 isoform 2 [Homo sapiens]; (4993:) Proteasome subunitalpha type 1 (Proteasome component C2) (Macropain subunit C2)(Multicatalytic endopeptidase complex subunit C2) (Proteasome nu chain)(30 kDa prosomal protein) (PROS-30); (4994:) Proteasome subunit alphatype 2 (Proteasome component C3) (Macropain subunit C3) (Multicatalyticendopeptidase complex subunit C3); (4995:) Proteasome subunit alpha type3 (Proteasome component C8) (Macropain subunit C8) (Multicatalyticendopeptidase complex subunit C8); (4996:) Proteasome subunit alpha type4 (Proteasome component C9) (Macropain subunit C9) (Multicatalyticendopeptidase complex subunit C9) (Proteasome subunit L); (4997:)Proteasome subunit beta type 1 (Proteasome component C5) (Macropainsubunit C5) (Multicatalytic endopeptidase complex subunit C5)(Proteasome gamma chain); (4998:) Proteasome subunit beta type 2(Proteasome component C7-I) (Macropain subunit C7-I) (Multicatalyticendopeptidase complex subunit C7-I); (4999:) Proteasome subunit betatype 3 (Proteasome theta chain) (Proteasome chain 13) (Proteasomecomponent C10-II); (5000:) Proteasome subunit beta type 4 precursor(Proteasome beta chain) (Macropain beta chain) (Multicatalyticendopeptidase complex beta chain) (Proteasome chain 3) (HSN3)(HsBPROS26); (5001:) proteasome subunit C2 [Homo sapiens]; (5002:)proteasome subunit C3 [Homo sapiens]; (5003:) proteasome subunit C5[Homo sapiens]; (5004:) proteasome subunit C8 [Homo sapiens]; (5005:)proteasome subunit C9 [Homo sapiens]; (5006:) proteasome subunitHsC10-II [Homo sapiens]; (5007:) proteasome subunit HsC7-I [Homosapiens]; (5008:) proteasome subunit HsN3 [Homo sapiens]; (5009:)proteasome subunit p40/Mov34 protein [Homo sapiens]; (5010:) proteasomesubunit X [Homo sapiens]; (5011:) proteasome subunit Y [Homo sapiens];(5012:) proteasome:SUBUNIT=HsC10-II; (5013:) proteasome:SUBUNIT=HsC7-I;(5014:) proteasome:SUBUNIT=HsN3; (5015:) protective protein forbeta-galactosidase [Homo sapiens]; (5016:) Protein arginineN-methyltransferase 1 (Interferon receptor 1-bound protein 4); (5017:)Protein arginine N-methyltransferase 3 (Heterogeneous nuclearribonucleoprotein methyltransferase-like protein 3); (5018:) Proteinarginine N-methyltransferase 6 (Heterogeneous nuclear ribonucleoproteinmethyltransferase-like protein 6); (5019:) Protein ariadne-1 homolog(ARI-1) (Ubiquitin-conjugating enzyme E2-binding protein 1)(UbCH7-binding protein) (UbcM4-interacting protein) (HHARI) (H7-AP2)(MOP-6); (5020:) protein disulfide isomerase-associated 3 precursor[Homo sapiens]; (5021:) protein disulfide isomerase-associated 4 [Homosapiens]; (5022:) protein disulfide isomerase-related protein; (5023:)Protein disulfide-isomerase A4 precursor (Protein ERp-72) (ERp72);(5024:) Protein disulfide-isomerase TXNDC10 precursor (Thioredoxindomain-containing protein 10) (Thioredoxin-related transmembrane protein3); (5025:) Protein FAM125A (CIN85/CD2AP family-binding protein);(5026:) protein kinase (EC 2.7.1.37), cAMP-dependent, type 1-betaregulatory chain—human; (5027:) Protein Kinase A (PKA); (5028:) ProteinKinase B (PKB); (5029:) Protein Kinase B (PKB); (5030:) protein kinase C(EC 2.7.1.-) beta-1—human; (5031:) Protein Kinase C (PKC); (5032:)Protein kinase C alpha type (PKC-alpha) (PKC-A); (5033:) Protein kinaseC beta type (PKC-beta) (PKC-B); (5034:) Protein kinase C delta type(nPKC-delta); (5035:) Protein kinase C epsilon type (nPKC-epsilon);(5036:) Protein kinase C eta type (nPKC-eta) (PKC-L); (5037:) Proteinkinase C gamma type (PKC-gamma); (5038:) Protein kinase C iota type(nPKC-iota) (Atypical protein kinase C-lambda/iota) (aPKC-lambda/iota)(PRKC-lambda/iota); (5039:) protein kinase C substrate 80K-H isoform 1[Homo sapiens]; (5040:) protein kinase C substrate 80K-H isoform 2 [Homosapiens]; (5041:) Protein kinase C theta type (nPKC-theta); (5042:)Protein kinase C zeta type (nPKC-zeta); (5043:) protein kinase C, alpha[Homo sapiens]; (5044:) protein kinase C, delta [Homo sapiens]; (5045:)protein kinase C, epsilon [Homo sapiens]; (5046:) protein kinase C,gamma [Homo sapiens]; (5047:) Protein Kinase C-alpha (PKC-alpha);(5048:) Protein Kinase C-beta (PKC-beta); (5049:) Protein Kinase C-delta(PKC-delta); (5050:) protein kinase CHK2 isoform a [Homo sapiens];(5051:) protein kinase CHK2 isoform b [Homo sapiens]; (5052:) proteinkinase CHK2 isoform c [Homo sapiens]; (5053:) protein kinase,cGMP-dependent, type I [Homo sapiens]; (5054:) protein kinase,DNA-activated, catalytic polypeptide [Homo sapiens]; (5055:) ProteinKinase-C Like 2 (PRKCL2); (5056:) Protein LMBR1L(Lipocalin-1-interacting membrane receptor) (Lipocalin-interactingmembrane receptor) (Limb region 1 protein homolog-like); (5057:) ProteinMTO1 homolog, mitochondrial precursor; (5058:) Protein N-terminalasparagine amidohydrolase (Protein NH2-terminal asparagine deamidase)(N-terminal Asn amidase) (NTN-amidase) (PNAD) (Protein NH2-terminalasparagine amidohydrolase) (PNAA); (5059:) protein O-fucosyltransferase1 isoform 1 precursor [Homo sapiens]; (5060:) proteinO-fucosyltransferase 1 isoform 2 precursor [Homo sapiens]; (5061:)Protein O-mannosyl-transferase 1(Dolichyl-phosphate-mannose—proteinmannosyltransferase 1); (5062:) Protein O-mannosyl-transferase2(Dolichyl-phosphate-mannose—protein mannosyltransferase 2); (5063:)Protein patched homolog 1 (PTC1) (PTC); (5064:) Protein patched homolog2 (PTC2); (5065:) protein phosphatase 1, catalytic subunit, alphaisoform 1 [Homo sapiens]; (5066:) protein phosphatase 1, catalyticsubunit, alpha isoform 2 [Homo sapiens]; (5067:) protein phosphatase 1,catalytic subunit, alpha isoform 3 [Homo sapiens]; (5068:) proteinphosphatase 1, catalytic subunit, gamma isoform [Homo sapiens]; (5069:)protein phosphatase 1G [Homo sapiens]; (5070:) protein phosphatase 1J(PP2C domain containing) [Homo sapiens]; (5071:) protein phosphatase 2,catalytic subunit, alpha isoform [Homo sapiens]; (5072:) proteinphosphatase 2, catalytic subunit, beta isoform [Homo sapiens]; (5073:)protein phosphatase 2, regulatory subunit B (B56), alpha isoform [Homosapiens]; (5074:) protein phosphatase 2, regulatory subunit B″, alphaisoform 1 [Homo sapiens]; (5075:) protein phosphatase 2, regulatorysubunit B″, alpha isoform 2 [Homo sapiens]; (5076:) protein phosphatase2, regulatory subunit B″, beta isoform 1 [Homo sapiens]; (5077:) proteinphosphatase 2, regulatory subunit B″, beta isoform 2 [Homo sapiens];(5078:) protein phosphatase 2A, regulatory subunit B′ isoform a [Homosapiens]; (5079:) protein phosphatase 2A, regulatory subunit B′ isoformb [Homo sapiens]; (5080:) protein phosphatase 2A, regulatory subunit B′isoform d [Homo sapiens]; (5081:) Protein phosphatase 2C isoform alpha(PP2C-alpha) (IA) (Protein phosphatase 1A); (5082:) Protein phosphatase2C isoform beta (PP2C-beta); (5083:) Protein preY, mitochondrialprecursor; (5084:) Protein Tyrosine Phosphatase 1B (PTP1B); (5085:)Protein tyrosine phosphatase type IVA protein 1 (Protein-tyrosinephosphatase 4a1) (Protein-tyrosine phosphatase of regenerating liver 1)(PRL-1) (PTP(CAAXI)); (5086:) Protein tyrosine phosphatase type IVAprotein 2 (Protein-tyrosine phosphatase 4a2) (Protein-tyrosinephosphatase of regenerating liver 2) (PRL-2) (PTP(CAAXII)) (HU-PP-1)(OV-1); (5087:) Protein tyrosine phosphatase type IVA protein 3(Protein-tyrosine phosphatase 4a3) (Protein-tyrosine phosphatase ofregenerating liver 3) (PRL-3) (PRL-R); (5088:) protein tyrosinephosphatase type IVA, member 1 [Homo sapiens]; (5089:) protein tyrosinephosphatase, non-receptor type 22 (lymphoid)isoform 1 [Homo sapiens];(5090:) protein tyrosine phosphatase, non-receptor type 22(lymphoid)isoform 2 [Homo sapiens]; (5091:) protein tyrosinephosphatase, receptor type, N precursor [Homo sapiens]; (5092:) proteinX [Homo sapiens]; (5093:) protein Z; (5094:) Protein-arginine deiminasetype-3 (Protein-arginine deiminase type III) (Peptidylarginine deiminaseIII); (5095:) Protein-arginine deiminase type-4 (Protein-argininedeiminase type IV) (Peptidylarginine deiminase IV) (HL-60 PAD); (5096:)proteinase 3 (serine proteinase, neutrophil, Wegener granulomatosisautoantigen) [Homo sapiens]; (5097:) Proteinase Activated Receptor-2(PAR-2); (5098:) Proteinase-activated receptor 1 precursor (PAR-1)(Thrombin receptor) (Coagulation factor II receptor); (5099:)Proteinase-activated receptor 2 precursor (PAR-2) (Thrombinreceptor-like 1) (Coagulation factor II receptor-like 1) (G-proteincoupled receptor II); (5100:) Proteinase-activated receptor 3 precursor(PAR-3) (Thrombin receptor-like 2) (Coagulation factor II receptor-like2); (5101:) Proteinase-activated receptor 4 precursor (PAR-4) (Thrombinreceptor-like 3) (Coagulation factor II receptor-like 3); (5102:)Protein-glutamine gamma-glutamyltransferase 5 (Transglutaminase-5)(TGase 5) (Transglutaminase X) (TGase X) (TGX) (TG(X)); (5103:)“Protein-glutamine gamma-glutamyltransferase E precursor (TGase E) (TGE)(TG(E)) (Transglutaminase-3) [Contains:) Protein-glutaminegamma-glutamyltransferase E 50 kDa non-catalytic chain;Protein-glutamine gamma-glutamyltransferase E 27 kDa catalytic chain].”;(5104:) Protein-glutamine gamma-glutamyltransferase K (TransglutaminaseK) (TGase K) (TGK) (TG(K)) (Transglutaminase-1) (Epidermal TGase);(5105:) protein-L-isoaspartate (D-aspartate) O-methyltransferase [Homosapiens]; (5106:) protein-O-mannosyltransferase 1 isoform a [Homosapiens]; (5107:) protein-O-mannosyltransferase 1 isoform b [Homosapiens]; (5108:) protein-O-mannosyltransferase 1 isoform c [Homosapiens]; (5109:) protein-tyrosine kinase (EC 2.7.1.112), receptor typetie precursor-human; (5110:) Protein-tyrosine sulfotransferase 1(Tyrosyl protein sulfotransferase-1) (TPST-1); (5111:)protein-tyrosine-phosphatase (EC 3.1.3.48), receptor type Hprecursor—human; (5112:) protein-tyrosine-phosphatase (EC 3.1.3.48),receptor type Op recursor—human; (5113:) “Prothrombin precursor(Coagulation factor 11) [Contains:) Activation peptide fragment 1;Activation peptide fragment 2; Thrombin light chain; Thrombin heavychain].”; (5114:) protooncogene protein 1 [Homo sapiens]; (5115:)Proto-oncogene tyrosine-protein kinase ABL1 (p150) (c-ABL)(Abelsonmurine leukemia viral oncogene homolog 1); (5116:)Proto-oncogene tyrosine-protein kinase MER precursor (C-mer) (Receptortyrosine kinase MerTK); (5117:) Proto-oncogene tyrosine-protein kinaseROS precursor (c-ros-1); (5118:) Protoporphyrinogen oxidase (PPO);(5119:) PRTD-NY3 [Homo sapiens]; (5120:) P-Selectin Activator; (5121:)Psychosine receptor (G-protein coupled receptor 65) (T celldeath-associated protein 8); (5122:) pterin carbinolamine dehydratase[Homo sapiens]; (5123:) pterin-4 alpha-carbinolamine dehydrataseprecursor [Homo sapiens]; (5124:) Pterin-4 alpha-carbinolaminedehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha(TCF1) [Homo sapiens]; (5125:) Pterin-4 alpha-carbinolaminedehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha(TCF1) 2 [Homo sapiens]; (5126:) pterin-4-a-carbinolamine dehydratase;(5127:) Pterin-4-alpha-carbinolamine dehydratase (PHS)(4-alpha-hydroxy-tetrahydropterin dehydratase)(Phenylalaninehydroxylase-stimulating protein) (Pterin carbinolaminedehydratase) (PCD) (Dimerization cofactor of hepatocyte nuclear factor1-alpha) (Dimerization cofactor of HNF1) (DCoH); (5128:)Pterin-4-alpha-carbinolamine dehydratase 2 (PHS 2)(4-alpha-hydroxy-tetrahydropterin dehydratase 2) (DcoH-like proteinDCoHm) (Dimerization cofactor of hepatocyte nuclear factor 1 frommuscle) (HNF1-alpha dimerization cofactor); (5129:) PTK2 proteintyrosine kinase 2 isoform a [Homo sapiens]; (5130:) PTK2 proteintyrosine kinase 2 isoform b [Homo sapiens]; (5131:) P-Type CalciumChannel Blocker; (5132:) Purine Nucleoside Phosphorylase (PNP); (5133:)purine nucleoside phosphorylase [Homo sapiens]; (5134:) putative1-aminocyclopropane-1-carboxylate synthase [Homo sapiens]; (5135:)putative acyl-CoA dehydrogenase [Homo sapiens]; (5136:) putativeb,b-carotene-9′,10′-dioxygenase [Homo sapiens]; (5137:) PutativeC->U-editing enzyme APOBEC-4 (Apolipoprotein BmRNA-editing enzymecatalytic polypeptide-like 4); (5138:) putative carotene dioxygenase[Homo sapiens]; (5139:) putative deubiquitinazing enzyme [Homo sapiens];(5140:) Putative G-protein coupled receptor 42; (5141:) PutativeG-protein coupled receptor 44 (Chemoattractant receptor-homologousmolecule expressed on Th2 cells) (CD294antigen); (5142:) “putativenon-ribosomal peptide synthetase NRPS1098; hNRPS1098 [Homo sapiens].”;(5143:) putative non-ribosomal peptide synthetase NRPS998 [Homosapiens]; (5144:) Putative P2Y purinoceptor 10 (P2Y10) (P2Y-likereceptor); (5145:) putative peroxisomal antioxidant enzyme [Homosapiens]; (5146:) putative protein O-mannosyltransferase [Homo sapiens];(5147:) putative pyroglutamyl-peptidase I [Homo sapiens]; (5148:)Putative Taste receptor type 2 member 12 (T2R12) (Taste receptor type 2member 26) (T2R26); (5149:) putative ubiquitin-conjugating enzyme E2variant [Homo sapiens]; (5150:) pVHL-interacting deubiquitinating enzyme1 type I [Homo sapiens]; (5151:) pVHL-interacting deubiquitinatingenzyme 1 type II [Homo sapiens]; (5152:) pVHL-interactingdeubiquitinating enzyme 2 [Homo sapiens]; (5153:) Pyridoxal kinase(Pyridoxine kinase); (5154:) pyridoxal kinase [Homo sapiens]; (5155:)Pyridoxal phosphate phosphatase (PLP phosphatase); (5156:) Pyridoxalphosphate phosphatase PHOSPHO2; (5157:) pyridoxine 5′-phosphate oxidase[Homo sapiens]; (5158:) pyroglutamyl-peptidase 1 [Homo sapiens]; (5159:)pyrophosphatase 1 [Homo sapiens]; (5160:) pyrroline 5-carboxylatesynthetase [Homo sapiens]; (5161:) pyrroline-5-carboxylate reductase 1isoform 1 [Homo sapiens]; (5162:) pyrroline-5-carboxylate reductase 1isoform 2 [Homo sapiens]; (5163:) pyrroline-5-carboxylate synthase [Homosapiens]; (5164:) pyrroline-5-carboxylate synthase long form [Homosapiens]; (5165:) pyrroline-5-carboxylate synthetase isoform 1 [Homosapiens]; (5166:) pyrroline-5-carboxylate synthetase isoform 2 [Homosapiens]; (5167:) Pyruvate carboxylase [Homo sapiens]; (5168:) pyruvatecarboxylase precursor [Homo sapiens]; (5169:) pyruvate carboxylaseprecursor; (5170:) Pyruvate carboxylase, mitochondrial precursor(Pyruvic carboxylase) (PCB); (5171:) pyruvate carboxylase; (5172:)“pyruvate carboxylase; pyruvate:carbon dioxide ligase [Homo sapiens].”;(5173:) pyruvate dehydrogenase (lipoamide) alpha 1 [Homo sapiens];(5174:) Pyruvate Dehydrogenase (PDH) Kinase; (5175:) pyruvatedehydrogenase complex protein X subunit precursor [Homo sapiens];(5176:) pyruvate dehydrogenase complex, component X [Homo sapiens];(5177:) Pyruvate dehydrogenase E1 component alpha subunit, somatic form,mitochondrial precursor (PDHE1-A type I); (5178:) Pyruvate dehydrogenaseE1 component alpha subunit, testis-specific form, mitochondrialprecursor (PDHE1-A type II); (5179:) Pyruvate dehydrogenase E1 componentsubunit beta, mitochondrial precursor (PDHE1-B); (5180:) PyruvateDehydrogenase Kinase 2 (PDHK2); (5181:) Pyruvate dehydrogenase protein Xcomponent, mitochondrial precursor (Dihydrolipoamidedehydrogenase-binding protein of pyruvate dehydrogenase complex)(Lipoyl-containing pyruvate dehydrogenase complex component X)(E3-binding protein) (E3BP) (proX); (5182:) pyruvate kinase (EC2.7.1.40), muscle splice form M1—human; (5183:) pyruvate kinase [Homosapiens]; (5184:) pyruvate kinase 3 isoform 1 [Homo sapiens]; (5185:)pyruvate kinase 3 isoform 1 variant [Homo sapiens]; (5186:) pyruvatekinase 3 isoform 2 [Homo sapiens]; (5187:) Pyruvate kinase isozymesM1/M2 (Pyruvate kinase muscle isozyme) (Pyruvate kinase 2/3) (Cytosolicthyroid hormone-binding protein) (CTHBP) (THBP1); (5188:) Pyruvatekinase isozymes R/L (R-type/L-type pyruvate kinase) (Red cell/liverpyruvate kinase) (Pyruvate kinase 1); (5189:) pyruvate kinase L [Homosapiens]; (5190:) pyruvate kinase M2 [Homo sapiens]; (5191:) pyruvatekinase PK-L isoenzyme [Homo sapiens]; (5192:) pyruvate kinase PK-Risoenzyme [Homo sapiens]; (5193:) Pyruvate kinase, liver and RBC [Homosapiens]; (5194:) pyruvate kinase, liver and RBC isoform 1 [Homosapiens]; (5195:) pyruvate kinase, liver and RBC isoform 2 [Homosapiens]; (5196:) Pyruvate kinase, muscle [Homo sapiens]; (5197:)pyruvate kinase; (5198:) carbon-dioxide ligase (ADP-forming); (5199:)Pyruvate:Ferredoxin Oxidoreductase (PFOR); (5200:) QTRT1 protein [Homosapiens]; (5201:) QTRTD1 protein [Homo sapiens]; (5202:) QueuinetRNA-ribosyltransferase (tRNA-guanine transglycosylase) (Guanineinsertion enzyme); (5203:) quinoid dihydropteridine reductase [Homosapiens]; (5204:) quinolinate phosphoribosyltransferase [Homo sapiens];(5205:) rabaptin, RAB GTPase binding effector protein 1 [Homo sapiens];(5206:) Rac GTPase activating protein 1 [Homo sapiens]; (5207:) RAD18[Homo sapiens]; (5208:) RAD51 homolog protein isoform 1 [Homo sapiens];(5209:) RAD51 homolog protein isoform 2 [Homo sapiens]; (5210:) RAD6homolog; (5211:) Raf Kinase (RKI); (5212:) ralA binding protein 1 [Homosapiens]; (5213:) RALBP1 associated Eps domain containing 2 [Homosapiens]; (5214:) Ran binding protein 11 [Homo sapiens]; (5215:) RANbinding protein 2 [Homo sapiens]; (5216:) RAN binding protein 9 [Homosapiens]; (5217:) Ran GTPase activating protein 1 [Homo sapiens];(5218:) Ran GTPase-activating protein 1; (5219:) Ran-binding protein 2(RanBP2) (Nuclear pore complex protein Nup358) (Nucleoporin Nup358) (358kDa nucleoporin) (P270); (5220:) Ran-binding protein 9 (RanBP9) (RanBP7)(Ran-binding protein M) (RanBPM) (BPM90) (BPM-L); (5221:) RanBP-type andC3HC4-type zinc finger containing 1 isoform 1 [Homo sapiens]; (5222:)RanBP-type and C3HC4-type zinc finger containing 1 isoform 2 [Homosapiens]; (5223:) RanBP-type and C3HC4-type zinc finger-containingprotein 1(Ubiquitin-conjugating enzyme 7-interacting protein 3)(Hepatitis B virus X-associated protein 4) (HBV-associated factor 4)(RING finger protein 54); (5224:) Ras-GTPase-activating proteinSH3-domain-binding protein [Homo sapiens]; (5225:) Ras-related C3botulinum toxin substrate 1 precursor (p21-Rac1) (Ras-like proteinTC25); (5226:) Ras-related C3 botulinum toxin substrate 2 precursor(p21-Rac2) (Small G protein) (GX); (5227:) Ras-related protein Rab-5A;(5228:) Ras-related protein Rab-5B; (5229:) Ras-related protein Rap-1Aprecursor (GTP-binding protein smg-p21A) (Ras-related protein Krev-1)(C21 KG) (G-22K); (5230:) Ras-related protein Rap-1b precursor(GTP-binding protein smgp21B); (5231:) Ras-related protein Rap-2a(RbBP-30); (5232:) rcUBE2S [Homo sapiens]; (5233:) Receptoractivity-modifying protein 1 precursor (CRLR activity-modifyingprotein 1) (Calcitonin-receptor-like receptor activity-modifying protein1); (5234:) Receptor activity-modifying protein 2 precursor (CRLRactivity-modifying protein 2) (Calcitonin-receptor-like receptoractivity-modifying protein 2); (5235:) Receptor activity-modifyingprotein 3 precursor (CRLR activity-modifying protein 3)(Calcitonin-receptor-like receptor activity-modifying protein 3);(5236:) Receptor Gamma (RXR Gamma); (5237:) Receptor tyrosine-proteinkinase erbB-2 precursor (p185erbB2) (C-erbB-2) (NEU proto-oncogene)(Tyrosine kinase-type cell surface receptor HER2) (MLN 19) (CD340antigen); (5238:) Receptor tyrosine-protein kinase erbB-3 precursor(c-erbB3) (Tyrosine kinase-type cell surface receptor HER3); (5239:)Receptor tyrosine-protein kinase erbB-4 precursor (p180erbB4) (Tyrosinekinase-type cell surface receptor HER4); (5240:) Receptor-binding cancerantigen expressed on SiSo cells (Cancer-associated surface antigenRCAS1) (Estrogen receptor-binding fragment-associated gene 9 protein);(5241:) receptor-interacting serine-threonine kinase 2 [Homo sapiens];(5242:) Receptor-type tyrosine-protein phosphatase delta precursor(Protein-tyrosine phosphatase delta) (R-PTP-delta); (5243:)Receptor-type tyrosine-protein phosphatase F precursor (LAR protein)(Leukocyte antigen related); (5244:) Receptor-type tyrosine-proteinphosphatase kappa precursor (Protein-tyrosine phosphatase kappa)(R-PTP-kappa); (5245:) Receptor-type tyrosine-protein phosphatase muprecursor (Protein-tyrosine phosphatase mu) (R-PTP-mu); (5246:)Receptor-type tyrosine-protein phosphatase N2 precursor (R-PTP-N2)(Islet cell autoantigen-related protein) (ICMR) (IAR) (Phogrin); (5247:)Receptor-type tyrosine-protein phosphatase O precursor (Glomerularepithelial protein 1) (Protein tyrosine phosphatase U2) (PTPase U2)(PTP-U2); (5248:) Receptor-type tyrosine-protein phosphatase R precursor(Protein-tyrosine phosphatase PCPTP1) (NC-PTPCOM1) (Ch-1 PTPase);(5249:) Receptor-type tyrosine-protein phosphatase S precursor (R-PTP-S)(Protein-tyrosine phosphatase sigma) (R-PTP-sigma); (5250:)Receptor-type tyrosine-protein phosphatase T precursor (R-PTP-T)(RPTP-rho); (5251:) Receptor-type tyrosine-protein phosphatase Uprecursor (R-PTP-U) (Protein-tyrosine phosphatase J) (PTP-J) (Pancreaticcarcinoma phosphatase 2) (PCP-2); (5252:) Receptor-type tyrosine-proteinphosphatase-like N precursor (R-PTP-N) (PTP IA-2) (Islet cell antigen512) (ICA 512) (Islet cell autoantigen 3); (5253:) RECK proteinprecursor [Homo sapiens]; (5254:) RecQ protein-like isoform 1 [Homosapiens]; (5255:) redox active peptide; (5256:) Red-sensitive opsin (Redcone photoreceptor pigment); (5257:) reductase, dihydrofolate; (5258:)Ref-1 [Homo sapiens]; (5259:) regenerating islet-derived 1 alphaprecursor [Homo sapiens]; (5260:) Relaxin receptor 1 (Relaxin familypeptide receptor 1) (Leucine-rich repeat-containing G-protein coupledreceptor 7); (5261:) Relaxin receptor 2 (Relaxin family peptide receptor2) (Leucine-rich repeat-containing G-protein coupled receptor 8)(G-protein coupled receptor affecting testicular descent) (G-proteincoupled receptor 106); (5262:) Relaxin-3 receptor 1 (RLN3 receptor 1)(Relaxin family peptide receptor 3) (Somatostatin- and angiotensin-likepeptide receptor) (G protein-coupled receptor SALPR) (GPCR135); (5263:)Relaxin-3 receptor 2 (Relaxin family peptide receptor 4) (G-proteincoupled receptor 100) (GPCR142); (5264:) Renin; (5265:) renin bindingprotein [Homo sapiens]; (5266:) Renin precursor (Angiotensinogenase);(5267:) Renin receptor precursor (Renin/prorenin receptor)(ATPaseH(+)-transporting lysosomal accessory protein 2)(ATPaseH(+)-transporting lysosomal-interacting protein 2) (VacuolarATPsynthase membrane sector-associated protein M8-9) (V-ATPaseM8.9subunit) (ATP6M8-9) (N14F) (ER-localized type I transmembraneadaptor) (Embryonic liver differentiation factor 10); (5268:) resistin[Homo sapiens]; (5269:) Ret Receptor Tyrosine Kinase Stimulator; (5270:)Reticulon-4 receptor precursor (Nogo receptor) (NgR) (Nogo-66receptor);(5271:) Reticulon-4 receptor-like 1 precursor (Nogo-66 receptor homolog2) (Nogo-66 receptor-related protein 3) (NgR3) (Nogo receptor-like 2);(5272:) Reticulon-4 receptor-like 2 precursor (Nogo-66 receptorhomolog 1) (Nogo-66 receptor-related protein 2) (NgR2) (Nogoreceptor-like 3); (5273:) retina copper-containing monoamine oxidase[Homo sapiens]; (5274:) Retinal dehydrogenase 1 (RalDH1) (RALDH1)(Aldehyde dehydrogenase family 1 member A1) (Aldehyde dehydrogenase,cytosolic) (ALHDII) (ALDH-E1); (5275:) Retinal guanylyl cyclase 1precursor (Guanylate cyclase 2D, retinal) (RETGC-1) (Rod outer segmentmembrane guanylate cyclase) (ROS-GC); (5276:) Retinal guanylyl cyclase 2precursor (Guanylate cyclase 2F, retinal) (RETGC-2) (Rod outer segmentmembrane guanylate cyclase 2) (ROS-GC2) (Guanylate cyclase F) (GC-F);(5277:) retinal pigment epithelium-specific protein 65 kDa [Homosapiens]; (5278:) retina-specific amine oxidase [Homo sapiens]; (5279:)Retina-specific copper amine oxidase precursor (RAO) (Amine oxidase[copper-containing]); (5280:) retinoblastoma 1 [Homo sapiens]; (5281:)retinoblastoma-like 2 (p130) [Homo sapiens]; (5282:) retinoic acidhydroxylase [Homo sapiens]; (5283:) Retinoic acid receptor alpha(RAR-alpha); (5284:) Retinoic acid receptor beta (RAR-beta)(RAR-epsilon) (HBV-activated protein); (5285:) Retinoic acid receptorgamma-1 (RAR-gamma-1); (5286:) Retinoic acid receptor gamma-2(RAR-gamma-2); (5287:) Retinoic acid receptor RXR-alpha (Retinoid Xreceptor alpha); (5288:) Retinoic acid receptor RXR-beta (Retinoid Xreceptor beta); (5289:) Retinoic acid receptor RXR-gamma (Retinoid Xreceptor gamma); (5290:) Retinoic Acid Receptor-Alpha (RAR Alpha);(5291:) Retinoic Acid Receptor-Beta (RAR Beta); (5292:) Retinoic AcidReceptor-Gamma (RAR Gamma); (5293:) Retinoic acid-induced protein 3(G-protein coupled receptor family C group 5 member A) (Retinoicacid-induced gene 1 protein) (RAIG-1) (Orphan G-protein couplingreceptor PEIG-1); (5294:) Retinoic X Receptor Alpha (RXR Alpha); (5295:)Retinoic X Receptor Beta (RXR Beta); (5296:) retinoid X receptor, alpha[Homo sapiens]; (5297:) Retinol Dehydrogenase; (5298:) Retinoldehydrogenase 12 (All-trans and 9-cis retinol dehydrogenase); (5299:)retinol dehydrogenase 12 (all-trans and 9-cis) [Homo sapiens]; (5300:)Retinol dehydrogenase 13; (5301:) retinol dehydrogenase 16 [Homosapiens]; (5302:) retinol dehydrogenase 5 (11-cis and 9-cis) [Homosapiens]; (5303:) retinol dehydrogenase 8 (all-trans) [Homo sapiens];(5304:) rhabdomyosarcoma antigen MU-RMS-40.10E [Homo sapiens]; (5305:)Rho GTPase Protein; (5306:) Rho-associated protein kinase 1(Rho-associated, coiled-coil-containing protein kinase 1) (p160 ROCK-1)(p160ROCK) (NY-REN-35 antigen); (5307:) Rho-associated protein kinase 2(Rho-associated, coiled-coil-containing protein kinase 2) (p164 ROCK-2)(Rho kinase 2); (5308:) Rho-associated, coiled-coil containing proteinkinase 1 [Homo sapiens]; (5309:) Rhodopsin (Opsin-2); (5310:)Rho-Kinase; (5311:) Rho-related GTP-binding protein RhoQ (Ras-relatedGTP-binding protein TC10); (5312:) Ribonuclease 4 precursor (RNase 4);(5313:) Ribonuclease H1 (RNase H1) (Ribonuclease H type II); (5314:)ribonuclease H1 [Homo sapiens]; (5315:) Ribonuclease H2 subunit A (RNaseH2 subunit A) (Ribonuclease HI subunit A) (Ribonuclease HI largesubunit) (RNase HI large subunit) (RNase H(35)) (Aicardi-Goutieressyndrome 4 protein) (AGS4); (5316:) ribonuclease HI, large subunit [Homosapiens]; (5317:) ribonuclease III, nuclear [Homo sapiens]; (5318:)ribonuclease, RNase A family, 4 precursor [Homo sapiens]; (5319:)Ribonucleoside-diphosphate reductase large subunit(Ribonucleoside-diphosphate reductase M1 subunit) (Ribonucleotidereductase large chain); (5320:) ribonucleoside-diphosphate reductase M1chain [Homo sapiens]; (5321:) Ribonucleotide Reductase (RR); (5322:)Ribose-phosphate pyrophosphokinase I (Phosphoribosyl pyrophosphatesynthetase I) (PRS-I) (PPRibP); (5323:) Ribose-phosphatepyrophosphokinase II (Phosphoribosyl pyrophosphate synthetase II)(PRS-II) (PPRibP); (5324:) Ribose-phosphate pyrophosphokinase III(Phosphoribosylpyrophosphate synthetase III) (PRS-III)(Phosphoribosylpyrophosphate synthetase 1-like 1); (5325:) Ribosomalprotein S6 kinase alpha-1 (S6K-alpha 1) (90 kDa ribosomal protein S6kinase 1) (p90-RSK1) (Ribosomal S6 kinase 1) (RSK-1) (pp 90RSK1)(p90S6K) (MAP kinase-activated protein kinase 1a) (MAPKAPK1A); (5326:)Ribosomal protein S6 kinase alpha-2 (S6K-alpha 2) (90 kDa ribosomalprotein S6 kinase 2) (p90-RSK 2) (Ribosomal S6 kinase 3) (RSK-3) (pp90RSK3) (MAP kinase-activated protein kinase 1c) (MAPKAPK1C); (5327:)Ribosomal protein S6 kinase alpha-3 (S6K-alpha 3) (90 kDa ribosomalprotein S6 kinase 3) (p90-RSK 3) (Ribosomal S6 kinase 2) (RSK-2) (pp90RSK2) (Insulin-stimulated protein kinase 1) (ISPK-1)(MAPkinase-activated protein kinase 1b) (MAPKAPK1B); (5328:) Ribosomalprotein S6 kinase alpha-4 (Nuclear mitogen- and stress-activated proteinkinase 2) (90 kDa ribosomal protein S6kinase 4) (Ribosomal proteinkinase B) (RSKB); (5329:) Ribosomal protein S6 kinase alpha-5 (Nuclearmitogen- and stress-activated protein kinase 1) (90 kDa ribosomalprotein S6kinase 5) (RSK-like protein kinase) (RSKL); (5330:) Ribosomalprotein S6 kinase alpha-6 (S6K-alpha 6) (90 kDa ribosomal protein S6kinase 6) (p90-RSK 6) (Ribosomal S6 kinase 4) (RSK-4) (pp 90RSK4);(5331:) Ribosomal protein S6 kinase beta-1 (Ribosomal protein S6kinase 1) (S6K) (S6K1) (70 kDa ribosomal protein S6 kinase 1) (p70 S6kinase alpha) (p70(S6K)-alpha) (p70-S6K) (P70S6K) (p70-alpha); (5332:)Ribosyldihydronicotinamide dehydrogenase [quinone] (NRH dehydrogenase[quinone] 2) (Quinone reductase 2) (QR2) (NRH:quinoneoxidoreductase 2);(5333:) RING finger and WD repeat domain protein 2 (Ubiquitin-proteinligase COP1) (Constitutive photomorphogenesis protein 1 homolog)(hCOP1); (5334:) RING finger protein 125 (T-cell RING activationprotein 1) (TRAC-1); (5335:) RING finger protein 139 (Translocation inrenal carcinoma onchromosome 8); (5336:) ring finger protein 139 [Homosapiens]; (5337:) ring finger protein 144 [Homo sapiens]; (5338:) ringfinger protein 2 [Homo sapiens]; (5339:) ring finger protein 25 [Homosapiens]; (5340:) RING finger protein 25; (5341:) RING finger protein 37(Ubiquitin-conjugating enzyme 7-interacting protein 5) (U-boxdomain-containing protein 5); (5342:) ring finger protein 41 isoform 1[Homo sapiens]; (5343:) ring finger protein 41 isoform 2 [Homo sapiens];(5344:) ring finger protein 7 isoform 1 [Homo sapiens]; (5345:) ringfinger protein 7 isoform 3 [Homo sapiens]; (5346:) RING-box protein 1(Rbx1) (Regulator of cullins 1) (RING finger protein 75) (Protein ZYP);(5347:) RING-box protein 2 (Rbx2) (RING finger protein 7) (Regulator ofcullins 2) (CKII beta-binding protein 1) (CKBBP1) (Sensitive toapoptosis gene protein); (5348:) RNA (guanine-7-) methyltransferase[Homo sapiens]; (5349:) RNA (guanine-N-7-) methyltransferase [Homosapiens]; (5350:) RNA 3′-terminal phosphate cyclase (RNA-3′-phosphatecyclase) (RNA cyclase); (5351:) RNA cyclase homolog [Homo sapiens];(5352:) RNA guanylyltransferase and 5′-phosphatase [Homo sapiens];(5353:) RNA lariat debranching enzyme [Homo sapiens]; (5354:) RNApolymerase I-associated factor PAF49 (Anti-sense to ERCC-1 protein)(ASE-1) (CD3-epsilon-associated protein) (CD3E-associated protein)(CAST); (5355:) RNA polymerase II transcription factor SIII p18 subunit;(5356:) RNA polymerase III subunit RPC155-A [Homo sapiens]; (5357:) RNApolymerase III subunit RPC155-B [Homo sapiens]; (5358:) RNA polymeraseIII subunit RPC155-C [Homo sapiens]; (5359:) RNA polymerase III subunitRPC155-D [Homo sapiens]; (5360:) RNA polymerase III subunit RPC62 [Homosapiens]; (5361:) RNA polymerase transcriptional regulation mediator,subunit 6homolog (Activator-recruited cofactor 33 kDa component) (ARC33)(NY-REN-28 antigen); (5362:) RNA-specific adenosine deaminase B1 isoform1 [Homo sapiens]; (5363:) RNA-specific adenosine deaminase B1 isoform 2[Homo sapiens]; (5364:) RNA-specific adenosine deaminase B1 isoform 3[Homo sapiens]; (5365:) RNA-specific adenosine deaminase B1 isoform 4[Homo sapiens]; (5366:) RNPEPL1 protein [Homo sapiens]; (5367:)Roundabout homolog 1 precursor (H-Robo-1) (Deleted in U twentytwenty);(5368:) Roundabout homolog 3 precursor (Roundabout-like protein 3);(5369:) Roundabout homolog 4 precursor (Magic roundabout); (5370:)RP11-235014.2 [Homo sapiens]; (5371:) RPE-retinal G protein-coupledreceptor; (5372:) “R-type pyruvate kinase; R-type PK [Homo sapiens].”;(5373:) Ryanodine Receptor 1 (RYR1); (5374:) Ryanodine receptor 1(Skeletal muscle-type ryanodine receptor) (RYR1) (RYR-1) (Skeletalmuscle calcium release channel); (5375:) Ryanodine receptor 2 (Cardiacmuscle-type ryanodine receptor) (RYR2) (RYR-2) (Cardiac muscle ryanodinereceptor-calcium release channel) (hRYR-2); (5376:) Ryanodine receptor 3(Brain-type ryanodine receptor) (RYR3) (RYR-3) (Brain ryanodinereceptor-calcium release channel); (5377:) S100 calcium-binding proteinA8 [Homo sapiens]; (5378:) S100 calcium-binding protein A9 [Homosapiens]; (5379:) SA [Homo sapiens]; (5380:) SA hypertension-associatedhomolog isoform 2 [Homo sapiens]; (5381:) S-adenosylhomocysteinehydrolase [Homo sapiens]; (5382:) S-adenosylmethionine decarboxylase(SAMDC); (5383:) S-adenosylmethionine decarboxylase 1 isoform 1precursor [Homo sapiens]; (5384:) S-adenosylmethionine decarboxylase 1isoform 2 [Homo sapiens]; (5385:) “S-adenosylmethionine decarboxylaseproenzyme (AdoMetDC) (SamDC)[Contains:) S-adenosylmethioninedecarboxylase alpha chain; S-adenosylmethionine decarboxylase betachain].”; (5386:) Salivary alpha-amylase precursor(1,4-alpha-D-glucanglucanohydrolase); (5387:) sarco/endoplasmicreticulum Ca2+-ATPase isoform a [Homo sapiens]; (5388:)sarco/endoplasmic reticulum Ca2+-ATPase isoform b [Homo sapiens];(5389:) sarco/endoplasmic reticulum Ca2+-ATPase isoform c [Homosapiens]; (5390:) sarco/endoplasmic reticulum Ca2+-ATPase isoform d[Homo sapiens]; (5391:) sarco/endoplasmic reticulum Ca2+-ATPase isoforme [Homo sapiens]; (5392:) sarco/endoplasmic reticulum Ca2+-ATPaseisoform f [Homo sapiens]; (5393:) Sarcoplasmic/endoplasmic reticulumcalcium ATPase 1 (Calcium pump 1) (SERCA1) (SR Ca(2+)-ATPase 1)(Calcium-transporting ATPasesarcoplasmic reticulum type, fast twitchskeletal muscle isoform) (Endoplasmic reticulum class 1/2 Ca(2+)ATPase); (5394:) Sarcoplasmic/endoplasmic reticulum calcium ATPase 2(Calcium pump 2) (SERCA2) (SR Ca(2+)-ATPase 2) (Calcium-transportingATPasesarcoplasmic reticulum type, slow twitch skeletal muscle isoform)(Endoplasmic reticulum class 1/2 Ca(2+) ATPase); (5395:)Sarcoplasmic/endoplasmic reticulum calcium ATPase 3 (Calcium pump 3)(SERCA3) (SR Ca(2+)-ATPase 3); (5396:) SARS Virus Protease; (5397:)scavenger mRNA decapping enzyme [Homo sapiens]; (5398:) Scavenger mRNAdecapping enzyme DcpS (DCS-1) (Hint-related7meGMP-directed hydrolase)(Histidine triad protein member 5) (HINT-5); (5399:) Scavenger receptorclass B member 1 (SRB1) (SR-BI) (CD36antigen-like 1) (CD36 and LIMPIIanalogous 1) (CLA-1) (Collagen type I receptor, thrombospondinreceptor-like 1); (5400:) scavenger receptor class B, member 1 [Homosapiens]; (5401:) Scavenger receptor class F member 2 precursor(Scavenger receptor expressed by endothelial cells 2 protein) (SREC-II)(SRECRP-1); (5402:) SDS protein [Homo sapiens]; (5403:) SDSL protein[Homo sapiens]; (5404:) SEC14-like 2 [Homo sapiens]; (5405:) SECISbinding protein 2 [Homo sapiens]; (5406:) Secreted Apoptosis-RelatedProtein 2 (SARP2); (5407:) Secretin Receptor (SCTR); (5408:) Secretinreceptor precursor (SCT-R); (5409:) Secretory Leukocyte Protease (SLPI);(5410:) Secretory Phospholipase A2 (sPLA2); (5411:) Secretory ProteinClusterin (sCLU); (5412:) selectin E precursor [Homo sapiens]; (5413:)selectin L precursor [Homo sapiens]; (5414:) selectin P ligand [Homosapiens]; (5415:) selectin P precursor [Homo sapiens]; (5416:)selenocysteine lyase [Homo sapiens]; (5417:) selenophosphate synthetase[Homo sapiens]; (5418:) selenophosphate synthetase 2 [Homo sapiens];(5419:) Semaphorin-4D precursor (Leukocyte activation antigen CD100)(BB18) (A8) (GR3); (5420:) Semicarbazide-Sensitive Amine Oxidase (SSAO);(5421:) Sentrin-specific protease 8 (Sentrin/SUMO-specific proteaseSENP8) (Protease, cysteine 2) (NEDD8-specific protease 1)(Deneddylase-1); (5422:) Separin (Separase) (Caspase-like protein ESPL1)(Extra spindle poles-like 1 protein); (5423:) sepiapterin reductase(7,8-dihydrobiopterin:NADP+oxidoreductase)[Homo sapiens]; (5424:)Sepiapterin reductase (SPR); (5425:) sepiapterin reductase; (5426:)Serase-1B [Homo sapiens]; (5427:) serine (or cysteine) proteinaseinhibitor, clade A (alpha-lantiproteinase, antitrypsin), member 1 [Homosapiens]; (5428:) serine (or cysteine) proteinase inhibitor, clade B(ovalbumin), member 2 [Homo sapiens]; (5429:) serine (or cysteine)proteinase inhibitor, clade B (ovalbumin), member 9 [Homo sapiens];(5430:) serine (or cysteine) proteinase inhibitor, clade I(neuroserpin), member 1 [Homo sapiens]; (5431:) serine dehydratase (EC4.2.1.13); (5432:) serine dehydratase [Homo sapiens]; (5433:) serinedehydratase-2 [Homo sapiens]; (5434:) serine dehydratase-like [Homosapiens]; (5435:) serine hydroxymethyltransferase 1 (soluble) isoform 1[Homo sapiens]; (5436:) serine hydroxymethyltransferase 1 (soluble)isoform 2 [Homo sapiens]; (5437:) Serine hydroxymethyltransferase,cytosolic (Serine methylase) (Glycine hydroxymethyltransferase) (SHMT);(5438:) Serine hydroxymethyltransferase, mitochondrial precursor (Serinemethylase) (Glycine hydroxymethyltransferase) (SHMT); (5439:) serinepalmitoyltransferase (SPT); (5440:) Serine palmitoyltransferase 1 (Longchain base biosynthesis protein1) (LCB1) (Serine-palmitoyl-CoAtransferase 1) (SPT 1) (SPT1); (5441:) Serine palmitoyltransferase 2(Long chain base biosynthesis protein2) (LCB 2) (Serine-palmitoyl-CoAtransferase 2) (SPT 2); (5442:) serine palmitoyltransferase subunit 1isoform a [Homo sapiens]; (5443:) serine palmitoyltransferase subunit 1isoform b [Homo sapiens]; (5444:) serine palmitoyltransferase, longchain base subunit 2 [Homo sapiens]; (5445:) serinepalmitoyltransferase, subunit I [Homo sapiens]; (5446:) serinepalmitoyltransferase, subunit II [Homo sapiens]; (5447:) serine proteaseinhibitor, Kazal type 1 [Homo sapiens]; (5448:) serine racemase [Homosapiens]; (5449:) Serine racemase; (5450:) serine/threonine kinase 16[Homo sapiens]; (5451:) Serine/threonine kinase NLK (Nemo-like kinase)(Protein LAK1); (5452:) Serine/threonine-protein kinase 25 (Sterile20/oxidant stress-response kinase 1) (Step 20/oxidant stress responsekinase 1) (SOK-1) (Step 20-like kinase); (5453:)Serine/threonine-protein kinase 3 (STE20-like kinase MST2) (MST-2)(Mammalian STE20-like protein kinase 2) (Serinelthreonine-protein kinaseKrs-1); (5454:) Serine/threonine-protein kinase 36 (Fused homolog);(5455:) Serine/threonine-protein kinase 38 (NDR1 protein kinase)(Nuclear Dbf2-related kinase 1); (5456:) Serine/threonine-protein kinase38-like (NDR2 protein kinase) (Nuclear Dbf2-related kinase 2); (5457:)Serine/threonine-protein kinase 4 (STE20-like kinase MST1) (MST-1)(Mammalian STE20-like protein kinase 1) (Serine/threonine-protein kinaseKrs-2); (5458:) Serine/threonine-protein kinase ATR (Ataxiatelangiectasia and Rad3-related protein) (FRAP-related protein 1);(5459:) Serine/threonine-protein kinase Chk2 (Cds1); (5460:)Serine/threonine-protein kinase D1 (nPKC-D1) (Protein kinase D) (Proteinkinase C mu type) (nPKC-mu); (5461:) Serine/threonine-protein kinase D2(nPKC-D2); (5462:) Serine/threonine-protein kinase D3 (Protein kinase Cnu type) (nPKC-nu) (Protein kinase EPK2); (5463:)Serine/threonine-protein kinase H1 (PSK-H1); (5464:)Serine/threonine-protein kinase ICK (Intestinal cell kinase) (hICK)(MAK-related kinase) (MRK) (Laryngeal cancer kinase 2) (LCK2); (5465:)Serine/threonine-protein kinase MARK1 (MAP/microtubuleaffinity-regulating kinase 1); (5466:) Serine/threonine-protein kinaseMARK2 (MAP/microtubule affinity-regulating kinase 2) (ELKL motif kinase)(EMK1) (PAR1 homolog); (5467:) Serine/threonine-protein kinase MRCKalpha (CDC42-binding protein kinase alpha) (Myotonic dystrophykinase-related CDC42-binding kinase alpha) (Myotonic dystrophy proteinkinase-like alpha) (MRCK alpha) (DMPK-like alpha); (5468:)Serine/threonine-protein kinase MRCK beta (CDC42-binding protein kinasebeta) (Myotonic dystrophy kinase-related CDC42-binding kinase beta)(Myotonic dystrophy protein kinase-like beta) (MRCK beta) (DMPK-likebeta); (5469:) Serine/threonine-protein kinase MRCK gamma (CDC42-bindingprotein kinase gamma) (Myotonic dystrophy kinase-related CDC42-bindingkinase gamma) (Myotonic dystrophy protein kinase-like alpha) (MRCKgamma) (DMPK-like gamma); (5470:) Serine/threonine-protein kinase MST4(STE20-like kinase MST4) (MST-4) (Mammalian STE20-like protein kinase 4)(Serine/threonine-protein kinase MASK) (Mst3 and SOK1-related kinase);(5471:) Serine/threonine-protein kinase NI (Protein kinase C-like 1)(Protein-kinase C-related kinase 1) (Protein kinase C-like PKN)(Serine-threonine protein kinase N) (Protein kinase PKN-alpha); (5472:)Serine/threonine-protein kinase N2 (Protein kinase C-like 2)(Protein-kinase C-related kinase 2); (5473:) Serine/threonine-proteinkinase Nek11 (NimA-related protein kinase 11) (Never in mitosisA-related kinase 11); (5474:) Serine/threonine-protein kinase Nek2(NimA-related protein kinase 2) (NimA-like protein kinase 1) (HSPK 21);(5475:) Serine/threonine-protein kinase Nek9 (NimA-related proteinkinase 9) (Never in mitosis A-related kinase 9) (Nercci kinase)(NIMA-related kinase 8) (Nek8); (5476:) Serine/threonine-protein kinaseNIM1; (5477:) Serine/threonine-protein kinase OSR1 (Oxidativestress-responsive 1 protein); (5478:) Serine/threonine-protein kinasePAK 1 (p21-activated kinase 1) (PAK-1) (P65-PAK) (Alpha-PAK); (5479:)Serine/threonine-protein kinase PAK 2 (p21-activated kinase 2) (PAK-2)(PAK65) (Gamma-PAK) (S6/H4 kinase); (5480:) Serine/threonine-proteinkinase PAK 3 (p21-activated kinase 3) (PAK-3) (Beta-PAK)(Oligophrenin-3); (5481:) Serine/threonine-protein kinase receptor R3precursor (SKR3) (Activin receptor-like kinase 1) (ALK-1) (TGF-Bsuperfamily receptor type I) (TSR-I); (5482:) Serine/threonine-proteinkinase SMG1 (SMG-1) (hSMG-1) (Lambda/iotaprotein kinase C-interactingprotein) (Lambda-interacting protein) (61 E3.4); (5483:)Serine/threonine-protein kinase SNF1-like kinase1(Serine/threonine-protein kinase SNF1LK); (5484:)Serine/threonine-protein kinase SNF1-like kinase 2 (Qin-induced kinase);(5485:) Serine/threonine-protein kinase SRPK1 (Serine/arginine-richprotein-specific kinase 1) (SR-protein-specific kinase 1) (SFRS proteinkinase 1); (5486:) Serine/threonine-protein kinase SRPK2(Serine/arginine-rich protein-specific kinase 2) (SR-protein-specifickinase 2) (SFRS protein kinase 2); (5487:) Serine/threonine-proteinkinase TBK1 (TANK-binding kinase 1) (T2K) (NF-kappa-B-activatingkinase); (5488:) Serine/threonine-protein kinase tousled-like 1(Tousled-like kinase 1) (PKU-beta); (5489:) Serine/threonine-proteinkinase tousled-like 2 (Tousled-like kinase 2) (PKU-alpha); (5490:)Serine/threonine-protein kinase VRK1 (Vaccinia-related kinase 1);(5491:) Serine/threonine-protein kinase WNK1 (Protein kinase with nolysine 1) (Protein kinase, lysine-deficient 1) (Kinase deficientprotein); (5492:) Serine/threonine-protein kinase WNK2 (Protein kinasewith no lysine-2) (Protein kinase, lysine-deficient 2); (5493:)Serine/threonine-protein kinase WNK3 (Protein kinase with no lysine-3)(Protein kinase, lysine-deficient 3); (5494:) Serine/threonine-proteinkinase WNK4 (Protein kinase with no lysine-4) (Protein kinase,lysine-deficient 4); (5495:) “Serine/threonine-proteinkinase/endoribonuclease IRE1 precursor (Inositol-requiring protein 1)(hIRE1p) (IRE1a) (Ire1-alpha) (Endoplasmic reticulum-to-nucleussignaling 1) [Includes:Serine/threonine-protein kinase;Endoribonuclease].”; (5496:) “Serine/threonine-proteinkinase/endoribonuclease IRE2 precursor (Inositol-requiring protein 2)(hIRE2p) (IRE1b) (Ire1-beta) (Endoplasmic reticulum-to-nucleus signaling2) [Includes:Serine/threonine-protein kinase; Endoribonuclease].”;(5497:) Serine/threonine-protein phosphatase 2A 48 kDa regulatorysubunit B(PP2A, subunit B, PR48 isoform); (5498:)Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit Balpha isoform (PP2A, subunit B, B-alpha isoform) (PP2A, subunit B,B55-alpha isoform) (PP2A, subunit B, PR55-alpha isoform) (PP2A, subunitB, R2-alpha isoform); (5499:) Serine/threonine-protein phosphatase 2A 55kDa regulatory subunit B beta isoform (PP2A, subunit B, B-beta isoform)(PP2A, subunit B, B55-beta isoform) (PP2A, subunit B, PR55-beta isoform)(PP2A, subunit B, R2-beta isoform); (5500:) Serine/threonine-proteinphosphatase 2A 55 kDa regulatory subunit B delta isoform (PP2A, subunitB, B-delta isoform) (PP2A, subunit B, B55-delta isoform) (PP2A, subunitB, PR55-delta isoform) (PP2A, subunit B, R2-delta isoform); (5501:)Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit Bgamma isoform (PP2A, subunit B, B-gamma isoform) (PP2A, subunit B,B55-gamma isoform) (PP2A, subunit B, PR55-gamma isoform) (PP2A, subunitB, R2-gamma isoform) (IMYPNO1); (5502:) Serine/threonine-proteinphosphatase 2A 56 kDa regulatory subunit alpha isoform (PP2A, B subunit,B′ alpha isoform) (PP2A, B subunit, B56 alpha isoform) (PP2A, B subunit,PR61 alpha isoform) (PP2A, B subunit, R5 alpha isoform); (5503:)Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit betaisoform (PP2A, B subunit, B′ beta isoform) (PP2A, B subunit, B56 betaisoform) (PP2A, B subunit, PR61 beta isoform) (PP2A, B subunit, R5 betaisoform); (5504:) Serine/threonine-protein phosphatase 2A 56 kDaregulatory subunit delta isoform (PP2A, B subunit, B′ delta isoform)(PP2A, B subunit, B56 delta isoform) (PP2A, B subunit, PR61 deltaisoform) (PP2A, B subunit, R5 delta isoform); (5505:)Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunitepsilon isoform (PP2A, B subunit, B′ epsilon isoform) (PP2A, B subunit,B56 epsilon isoform) (PP2A, B subunit, PR61 epsilon isoform) (PP2A, Bsubunit, R5 epsilon isoform); (5506:) Serine/threonine-proteinphosphatase 2A 56 kDa regulatory subunit gamma isoform (PP2A, B subunit,B′ gamma isoform) (PP2A, B subunit, B56 gamma isoform) (PP2A, B subunit,PR61 gamma isoform) (PP2A, B subunit, R5 gamma isoform) (NY-REN-29antigen); (5507:) Serine/threonine-protein phosphatase 2A 65 kDaregulatory subunit A beta isoform (PP2A, subunit A, PR65-beta isoform)(PP2A, subunit A, R1-beta isoform); (5508:) Serine/threonine-proteinphosphatase 2A 65 kDa regulatory subunit A alpha isoform (PP2A, subunitA, PR65-alpha isoform) (PP2A, subunit A, R1-alpha isoform) (Medium tumorantigen-associated 61 kDa protein); (5509:) Serine/threonine-proteinphosphatase 2A 72/130 kDa regulatory subunit B (PP2A, subunit B,B″-PR72/PR130) (PP2A, subunit B, B72/B130 isoforms) (PP2A, subunit B,PR72/PR130 isoforms) (PP2A, subunit B, R3 isoform); (5510:)Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform(PP2A-alpha) (Replication protein C) (RP-C); (5511:)Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform(PP2A-beta); (5512:) Serine/threonine-protein phosphatase 2A regulatorysubunit B′(PP2A, subunit B′, PR53 isoform) (Phosphotyrosyl phosphataseactivator) (PTPA); (5513:) Serine/threonine-protein phosphatase withEF-hands 1 (PPEF-1) (Protein phosphatase with EF calcium-binding domain)(PPEF) (Serine/threonine-protein phosphatase 7) (PP7); (5514:)Serine/threonine-protein phosphatase with EF-hands 2 (PPEF-2); (5515:)Serine-protein kinase ATM (Ataxia telangiectasia mutated) (A-T,mutated); (5516:) serum albumin precursor [Homo sapiens]; (5517:) Serumparaoxonase/arylesterase 1 (PON1) (Serumaryidialkylphosphatase 1)(A-esterase 1) (Aromatic esterase 1) (K-45); (5518:)serum/glucocorticoid regulated kinase [Homo sapiens]; (5519:) seryl-tRNAsynthetase [Homo sapiens]; (5520:) SET and MYND domain-containingprotein 3 (Zinc finger MYND domain-containing protein 1); (5521:) SETdomain-containing protein 7 [Homo sapiens]; (5522:) SH3-containingGRB2-like protein 2 (Endophilin-1) (Endophilin-A1) (SH3 domain protein2A) (EEN-B1); (5523:) SH3-domain kinase-binding protein 1(Cbl-interacting protein of 85 kDa) (Human Src-family kinase-bindingprotein 1) (HSB-1) (CD2-binding protein 3) (CD2BP3); (5524:)short/branched chain acyl-CoA dehydrogenase [Homo sapiens]; (5525:)Short/branched chain specific acyl-CoA dehydrogenase, mitochondrialprecursor (SBCAD) (2-methyl branched chain acyl-CoA dehydrogenase)(2-MEBCAD) (2-methylbutyryl-coenzyme A dehydrogenase)(2-methylbutyryl-CoA dehydrogenase); (5526:) sialidase 2 [Homo sapiens];(5527:) sialidase 3 [Homo sapiens]; (5528:) sialidase 4 [Homo sapiens];(5529:) Sialidase-1 precursor (Lysosomal sialidase)(N-acetyl-alpha-neuraminidase 1) (Acetylneuraminyl hydrolase)(G9sialidase); (5530:) sialyltransferase 1 isoform a [Homo sapiens];(5531:) sialyltransferase 1 isoform b [Homo sapiens]; (5532:)sialyltransferase 6 isoform a [Homo sapiens]; (5533:) sialyltransferase6 isoform b [Homo sapiens]; (5534:) sialyltransferase 6 isoform c [Homosapiens]; (5535:) sialyltransferase 6 isoform d [Homo sapiens]; (5536:)sialyltransferase 6 isoform e [Homo sapiens]; (5537:) sialyltransferase6 isoform f [Homo sapiens]; (5538:) sialyltransferase 6 isoform g [Homosapiens]; (5539:) sialyltransferase 6 isoform h [Homo sapiens]; (5540:)sialyltransferase 6 isoform i [Homo sapiens]; (5541:) sialyltransferase6 isoform j [Homo sapiens]; (5542:) Sigma Receptor; (5543:) Sigma1Receptor; (5544:) Sigma2 Receptor; (5545:) signal peptide peptidase-like2β isoform 2 [Homo sapiens]; (5546:) signal peptide peptidase-like 2βisoform 3 [Homo sapiens]; (5547:) Signal recognition particle receptorsubunit alpha (SR-alpha) (Docking protein alpha) (DP-alpha); (5548:)Signal recognition particle receptor subunit beta (SR-beta) (ProteinAPMCF1); (5549:) Signal Transducer and Activator of Transcription 1(STAT1); (5550:) Signal Transducer and Activator of Transcription 3(STAT3); (5551:) Signal Transducer and Activator of Transcription 4(STAT4); (5552:) Signal transducing adapter molecule 2 (STAM-2); (5553:)signal transducing adaptor molecule 1 [Homo sapiens]; (5554:) signaltransducing adaptor molecule 2 [Homo sapiens]; (5555:) Signaltransduction protein CBL-C(SH3-binding protein CBL-C) (CBL-3) (RINGfinger protein 57); (5556:) Signaling lymphocytic activation moleculeprecursor (IPO-3) (CD150antigen) (CDw150); (5557:) Single-strandselective monofunctional uracil DNA glycosylase; (5558:) Sirtunin 1(SIRT1); (5559:) skeletal myosin light chain kinase [Homo sapiens];(5560:) Skin Protease (SPI); (5561:) SLAM family member 5 precursor(Signaling lymphocytic activation molecule 5) (Leukocyte differentiationantigen CD84) (CD84 antigen) (Cell surface antigen MAX.3) (Hly9-beta);(5562:) SLAM family member 6 precursor (NK-T-B-antigen) (NTB-A)(Activating NK receptor); (5563:) SLAM family member 7 precursor(CD2-like receptor activating cytotoxic cells) (CRACC) (Protein 19A)(CD2 subset 1) (Novel Ly9) (Membrane protein FOAP-12) (CD319 antigen);(5564:) SLC27A1 protein [Homo sapiens]; (5565:) SLC27A3 protein [Homosapiens]; (5566:) Smad ubiquitination regulatory factor 1(Ubiquitin—protein ligase SMURF1) (Smad-specific E3 ubiquitin ligase 1)(hSMURF1); (5567:) Smad ubiquitination regulatory factor 2(Ubiquitin—protein ligase SMURF2) (Smad-specific E3 ubiquitin ligase 2)(hSMURF2); (5568:) “Small inducible cytokine A14 precursor (CCL14)(Chemokine CC-1/CC-3) (HCC-1/HCC-3) (HCC-1(1-74)) (NCC-2)[Contains:HCC-1(3-74); HCC-1(4-74); HCC-1(9-74)].”; (5569:) smallinducible cytokine A2 precursor [Homo sapiens]; (5570:) “Small induciblecytokine A5 precursor (CCL5) (T-cell-specific RANTES protein)(SIS-delta) (T cell-specific protein P228) (TCP228)[Contains:)RANTES(3-68); RANTES(4-68)].”; (5571:) small inducible cytokine B10precursor [Homo sapiens]; (5572:) Small ubiquitin-related modifier 4precursor (SUMO-4) (Small ubiquitin-like protein 4); (5573:)S-methyl-5-thioadenosine phosphorylase(5′-methylthioadenosinephosphorylase) (MTA phosphorylase) (MTAPase);(5574:) Smoothened homolog precursor (SMO) (Gx protein); (5575:) SMT3suppressor of mif two 3 homolog 1 isoform a precursor [Homo sapiens];(5576:) SMT3 suppressor of mif two 3 homolog 1 isoform b precursor [Homosapiens]; (5577:) Sn1-specific diacylglycerol lipase alpha (DGL-alpha)(Neural stem cell-derived dendrite regulator); (5578:) Sn1-specificdiacylglycerol lipase beta (DGL-beta) (KCCR13L); (5579:) snakevenom-like protease [Homo sapiens]; (5580:) SNF-relatedserine/threonine-protein kinase (SNF1-related kinase); (5581:) Sodiumbicarbonate cotransporter 3 (Sodium bicarbonate cotransporter 2) (Sodiumbicarbonate cotransporter 2b) (Bicarbonate transporter) (Solute carrierfamily 4 member 7); (5582:) Sodium Hydrogen Exchange (NHE); (5583:)Sodium Hydrogen Exchange Isoform-1 (NHE-1); (5584:) Sodium HydrogenExchange Isoform-3 (NHE-3); (5585:) Sodium/calcium exchanger 1 precursor(Na(+)/Ca(2+)-exchange protein1); (5586:) Sodium/calcium exchanger 2precursor (Na(+)/Ca(2+)-exchange protein2); (5587:) Sodium/calciumexchanger 3 precursor (Na(+)/Ca(2+)-exchange protein3); (5588:)Sodium/nucleoside cotransporter 2 (Na(+)/nucleoside cotransporter 2)(Sodium-coupled nucleoside transporter 2) (Concentrative nucleosidetransporter 2) (CNT 2) (hCNT2) (Sodium/purine nucleoside co-transporter)(SPNT); (5589:) Sodium/potassium-transporting ATPase alpha-1 chainprecursor (Sodium pump 1) (Na+/K+ ATPase 1); (5590:)Sodium/potassium-transporting ATPase alpha-2 chain precursor (Sodiumpump 2) (Na+/K+ ATPase 2); (5591:) Sodium/potassium-transporting ATPasealpha-3 chain (Sodium pump 3) (Na+/K+ ATPase 3) (Alpha(III)); (5592:)Sodium/potassium-transporting ATPase alpha-4 chain (Sodium pump 4)(Na+/K+ ATPase 4); (5593:) Sodium/potassium-transporting ATPase subunitbeta-1 (Sodium/potassium-dependent ATPase beta-1 subunit); (5594:)Sodium/potassium-transporting ATPase subunitbeta-2(Sodium/potassium-dependent ATPase beta-2 subunit); (5595:)Sodium/potassium-transporting ATPase subunitbeta-3(Sodium/potassium-dependent ATPase beta-3 subunit) (ATPB-3)(CD298antigen); (5596:) Sodium-Chloride Cotransporter (NCC); (5597:)Sodium-dependent phosphate transporter 1 (Solute carrier family20member 1) (Phosphate transporter 1) (PiT-1) (Gibbon ape leukemia virusreceptor 1) (GLVR-1) (Leukemia virus receptor 1 homolog); (5598:)Sodium-Glucose Cotransporter (SGLT); (5599:) Sodium-GlucoseCotransporter Type 1 (SGLT1); (5600:) Sodium-Glucose Cotransporter Type2 (SGLT2); (5601:) Sodium-Potassium ATPase; (5602:)Sodium-Potassium-Chloride Cotransporter; (5603:) Solublecalcium-activated nucleotidase 1 (SCAN-1) (Apyrase homolog) (PutativeNF-kappa-B-activating protein 107) (Putative MAPK-activating proteinPM09); (5604:) soluble calcium-activated nucleotidase 1 [Homo sapiens];(5605:) solute carrier family 2 (facilitated glucose transporter),member 1 [Homo sapiens]; (5606:) solute carrier family 27 (fatty acidtransporter), member 2 [Homo sapiens]; (5607:) solute carrier family 7(cationic amino acid transporter, y+system), member 1 [Homo sapiens];(5608:) solute carrier family 7, member 2 isoform 1 [Homo sapiens];(5609:) solute carrier family 7, member 2 isoform 2 [Homo sapiens];(5610:) Somatostatin Receptor (SSTR); (5611:) Somatostatin Receptor 1(SSTR1); (5612:) Somatostatin Receptor 2 (SSTR2); (5613:) SomatostatinReceptor 3 (SSTR3); (5614:) Somatostatin Receptor 5 (SSTR5); (5615:)Somatostatin receptor type 1 (SS1R) (SRIF-2); (5616:) Somatostatinreceptor type 2 (SS2R) (SRIF-1); (5617:) Somatostatin receptor type 3(SS3R) (SSR-28); (5618:) Somatostatin receptor type 4 (SS4R); (5619:)Somatostatin receptor type 5 (SS5R); (5620:) Sorbitol dehydrogenase(L-iditol 2-dehydrogenase); (5621:) sorbitol dehydrogenase [Homosapiens]; (5622:) Sortilin precursor (Neurotensin receptor 3) (NTR3)(NT3) (Glycoprotein 95) (Gp95) (100 kDa NT receptor); (5623:)sortilin-related receptor containing LDLR class A repeats preproprotein[Homo sapiens]; (5624:) Sortilin-related receptor precursor (Sortingprotein-related receptor containing LDLR class A repeats) (SorLA)(SorLA-1) (Low-density lipoprotein receptor relative with 11ligand-binding repeats) (LDLR relative with 11 ligand-binding repeats)(LR11); (5625:) Sorting nexin-1; (5626:) Sorting nexin-2(Transformation-related gene 9 protein) (TRG-9); (5627:) Sp1transcription factor [Homo sapiens]; (5628:) spectrin, alpha,erythrocytic 1 [Homo sapiens]; (5629:) spen homolog, transcriptionalregulator [Homo sapiens]; (5630:) sperm adhesion molecule 1 isoform 1[Homo sapiens]; (5631:) sperm adhesion molecule 1 isoform 2 [Homosapiens]; (5632:) Spermidine synthase (Putrescine aminopropyltransferase) (SPDSY); (5633:) spermidine synthase [Homo sapiens];(5634:) Spermidine/Spermine NI-Acetyltransferase (SSAT); (5635:)spermidine/spermine NI-acetyltransferase [Homo sapiens]; (5636:)Spermine oxidase (Polyamine oxidase 1) (PAO-1) (PAOh1); (5637:) sperminesynthase [Homo sapiens]; (5638:) S-phase kinase-associated protein 1Aisoform a [Homo sapiens]; (5639:) S-phase kinase-associated protein 1Aisoform b [Homo sapiens]; (5640:) S-phase kinase-associated protein 2isoform 1 [Homo sapiens]; (5641:) S-phase kinase-associated protein 2isoform 2 [Homo sapiens]; (5642:) sphingomyelin phosphodiesterase (EC3.1.4.12)—human (fragments); (5643:) sphingomyelin phosphodiesterase[Homo sapiens]; (5644:) sphingomyelin phosphodiesterase 1, acidlysosomal isoform 1precursor [Homo sapiens]; (5645:) sphingomyelinphosphodiesterase 1, acid lysosomal isoform 2precursor [Homo sapiens];(5646:) Sphingomyelin phosphodiesterase 3 (Neutral sphingomyelinase 2)(Neutral sphingomyelinase 11) (nSMase 2) (nSMase-2); (5647:)Sphingomyelin phosphodiesterase precursor (Acid sphingomyelinase)(aSMase); (5648:) Sphingosine 1-Phosphate (SIP) Receptor; (5649:)Sphingosine 1-Phosphate Receptor 1 (SI P1); (5650:) Sphingosine1-phosphate receptor Edg-1 (Sphingosine 1-phosphate receptor 1) (SI P1);(5651:) Sphingosine 1-phosphate receptor Edg-3 (S1P receptor Edg-3)(Endothelial differentiation G-protein coupled receptor 3) (Sphingosine1-phosphate receptor 3) (S1P3); (5652:) Sphingosine 1-phosphate receptorEdg-5 (S1P receptor Edg-5) (Endothelial differentiation G-proteincoupled receptor 5) (Sphingosine 1-phosphate receptor 2) (S1P2); (5653:)Sphingosine 1-phosphate receptor Edg-6 (SIP receptor Edg-6) (Endothelialdifferentiation G-protein coupled receptor 6) (Sphingosine 1-phosphatereceptor 4) (S1P4); (5654:) Sphingosine 1-phosphate receptor Edg-8(Endothelial differentiation sphingolipid G-protein-coupled receptor 8)(Sphingosine 1-phosphate receptor 5) (S1P5); (5655:) Sphingosine1-phosphate receptor GPR6 (G-protein coupled receptor6); (5656:)sphingosine kinase 1 isoform 1 [Homo sapiens]; (5657:) sphingosinekinase 1 isoform 2 [Homo sapiens]; (5658:) Sphingosylphosphorylcholinereceptor (Ovarian cancer G-protein coupled receptor 1) (OGR-1)(G-protein coupled receptor 68) (GPR12A); (5659:) Spleen Tyrosine Kinase(Syk); (5660:) Squalene Synthase; (5661:) Squalene synthetase (SQS) (SS)(Farnesyl-diphosphate farnesyltransferase) (FPP:FPPfarnesyltransferase); (5662:) Sqv-8-like protein [Homo sapiens]; (5663:)Src Homology-2-Containing Protein Tyrosine Phosphatase-1 (SHP-1);(5664:) Src Tyrosine Kinase (STK); (5665:) SRC/ABL Kinase; (5666:) SRPRNA 3′ adenylating enzyme/pap2 [Homo sapiens]; (5667:) SRR [Homosapiens]; (5668:) ST3 beta-galactoside alpha-2,3-sialyltransferase 5isoform 1 [Homo sapiens]; (5669:) ST3 beta-galactosidealpha-2,3-sialyltransferase 5 isoform 2 [Homo sapiens]; (5670:) ST8alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 [Homo sapiens];(567-1:) Stabilin-1 precursor (FEEL-1 protein) (MS-1 antigen); (5672:)Stabilin-2 precursor (FEEL-2 protein) (Fasciclin EGF-like laminin-typeEGF-like and link domain-containing scavenger receptor1) (FAS1 EGF-likeand X-link domain-containing adhesion molecule 2) (Hyaluronan receptorfor endocytosis) [Contains:) 190 kDa formstabilin-2 (190 kDa hyaluronanreceptor for endocytosis)]; (5673:) STAM binding protein [Homo sapiens];(5674:) STAM-binding protein (Associated molecule with the SH3 domain ofSTAM); (5675:) Staphylococcus aureus Methionyl-tRNA Synthetase (MetS);(5676:) stearoyl-CoA desaturase [Homo sapiens]; (5677:) stearoyl-CoAdesaturase 4 isoform a [Homo sapiens]; (5678:) stearoyl-CoA desaturase 4isoform b [Homo sapiens]; (5679:) steroid dehydrogenase homolog [Homosapiens]; (5680:) Steroid hormone receptor ERR1 (Estrogen-relatedreceptor, alpha) (ERR-alpha) (Estrogen receptor-like 1); (5681:) Steroidhormone receptor ERR2 (Estrogen-related receptor, beta) (ERR-beta)(Estrogen receptor-like 2) (ERR beta-2); (5682:) Steroid receptor RNAactivator 1 (Steroid receptor RNA activator protein) (SRAP); (5683:)steroid sulfatase [Homo sapiens]; (5684:) Steroid X Receptor (SXR);(5685:) steroid-5-alpha-reductase 1 [Homo sapiens]; (5686:)Steroidogenic factor 1 (STF-1) (SF-1) (Adrenal 4-binding protein)(Steroid hormone receptor Ad4BP) (Fushi tarazu factor homolog 1);(5687:) sterol O-acyltransferase (acyl-Coenzyme A:)cholesterolacyltransferase) 1 [Homo sapiens]; (5688:)sterol-C5-desaturase-like [Homo sapiens]; (5689:) steryl-sulfataseprecursor [Homo sapiens]; (5690:) Stomach Acid Neutralizer; (5691:)Stratum Corneum Chymotryptic Enzyme (SCCE); (5692:) stratum corneumchymotryptic enzyme [Homo sapiens]; (5693:) stratum corneum chymotrypticenzyme preproprotein [Homo sapiens]; (5694:) stratum corneumchymotryptic enzyme; (5695:) stratum corneum tryptic enzyme [Homosapiens]; (5696:) Stress-Associated Endoplasmic Reticulum Protein 1(SERP1); (5697:) Substance-K receptor (SKR) (Neurokinin A receptor)(NK-2 receptor) (NK-2R) (Tachykinin receptor 2); (5698:) Substance-Preceptor (SPR) (NK-1 receptor) (NK-1R) (Tachykinin receptor 1); (5699:)Substrate Binding And Catalysis By Glutathione Reductase As Derived FromRefined Enzyme:) Substrate Crystal Structures At 2 Angstroms Resolution;(5700:) subtilisin-like proprotein convertase (EC 3.4.21.-)homolog-human; (5701:) succinate dehydrogenase complex, subunit A,flavoprotein precursor[Homo sapiens]; (5702:) succinate dehydrogenasecomplex, subunit B, iron sulfur (Ip) [Homo sapiens]; (5703:) succinatedehydrogenase complex, subunit C isoform 1 precursor[Homo sapiens];(5704:) succinate dehydrogenase complex, subunit C isoform 2precursor[Homo sapiens]; (5705:) succinate dehydrogenase complex,subunit C isoform 3 precursor[Homo sapiens]; (5706:) succinatedehydrogenase complex, subunit C isoform 4 precursor[Homo sapiens];(5707:) succinate dehydrogenase complex, subunit D precursor [Homosapiens]; (5708:) succinate dehydrogenase flavoprotein subunit; (5709:)Succinate receptor 1 (G-protein coupled receptor 91) (P2Y purinoceptor1-like); (5710:) Succinate semialdehyde dehydrogenase, mitochondrialprecursor (NAD(+)-dependent succinic semialdehyde dehydrogenase);(5711:) succinate-CoA ligase, ADP-forming, beta subunit [Homo sapiens];(5712:) succinyl CoA:3-oxoacid CoA transferase precursor; (5713:)Succinyl-CoA ligase [ADP-forming] beta-chain, mitochondrial precursor(Succinyl-CoA synthetase, betaA chain) (SCS-betaA) (ATP-specificsuccinyl-CoA synthetase subunit beta) (NY-REN-39antigen); (5714:)Succinyl-CoA:3-ketoacid-coenzyme A transferase 1, mitochondrialprecursor (Somatic-type succinyl CoA:3-oxoacid CoA-transferase)(Scot-S); (5715:) Succinyl-CoA:3-ketoacid-coenzyme A transferase 2,mitochondrial precursor (Testis-specific succinyl CoA:3-oxoacidCoA-transferase) (SCOT-t); (5716:) “Sucrase-isomaltase, intestinal[Contains:) Sucrase; Isomaltase].”; (5717:) Sulfatase; (5718:) sulfatasemodifying factor 1 [Homo sapiens]; (5719:) sulfatase modifying factor 2isoform a precursor [Homo sapiens]; (5720:) sulfatase modifying factor 2isoform b precursor [Homo sapiens]; (5721:) sulfatase modifying factor 2isoform c precursor [Homo sapiens]; (5722:) sulfatase modifying factor 2isoform d precursor [Homo sapiens]; (5723:) Sulfatase-modifying factor 1precursor (C-alpha-formyglycine-generating enzyme 1); (5724:)Sulfatase-modifying factor 2 precursor (C-alpha-formyglycine-generatingenzyme 2); (5725:) sulfite oxidase [Homo sapiens]; (5726:) Sulfiteoxidase, mitochondrial precursor; (5727:) Sulfonylurea Receptor 1(SUR1); (5728:) Sulfotransferase 1A1 (Aryl sulfotransferase 1)(Phenolsulfotransferase 1) (Phenol-sulfating phenol sulfotransferase 1)(P-PST 1) (Thermostable phenol sulfotransferase) (Ts-PST) (HAST1/HAST2)(ST1A3); (5729:) sulfotransferase family, cytosolic, 1A,phenol-preferring, member 1 isoform a [Homo sapiens]; (5730:)sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1isoform b [Homo sapiens]; (5731:) sulfotransferase family, cytosolic,1A, phenol-preferring, member 2 [Homo sapiens]; (5732:) sulfotransferasefamily, cytosolic, 1A, phenol-preferring, member 3 [Homo sapiens];(5733:) sulfotransferase family, cytosolic, 1A, phenol-preferring,member 4 [Homo sapiens]; (5734:) sulfotransferase family, cytosolic, 2A,dehydroepiandrosterone-preferring, member 1 [Homo sapiens]; (5735:)sulfotransferase family, cytosolic, 2B, member 1 isoform a [Homosapiens]; (5736:) sulfotransferase family, cytosolic, 2B, member 1isoform b [Homo sapiens]; (5737:) SUMO1 activating enzyme subunit 1[Homo sapiens]; (5738:) SUMO-1 activating enzyme subunit 1 [Homosapiens]; (5739:) SUMO1 activating enzyme subunit 2 [Homo sapiens];(5740:) SUMO-1 activating enzyme subunit 2 [Homo sapiens]; (5741:)SUMO-1 activating enzyme subunit 2 variant [Homo sapiens]; (5742:)SUMO-1-activating enzyme E1 C subunit [Homo sapiens]; (5743:)SUMO-1-activating enzyme E1 N subunit [Homo sapiens]; (5744:)SUMO-1-conjugating enzyme UBC9 (SUMO-1-protein ligase)(Ubiquitin-conjugating enzyme E2 I) (Ubiquitin-protein ligase I)(Ubiquitin carrier protein 1) (Ubiquitin carrier protein 9) (p18);(5745:) Superoxide Dismutase (SOD) Mimetic; (5746:) Superoxide dismutase[Cu—Zn]; (5747:) Superoxide Dismutase 1 (SOD1); (5748:) superoxidedismutase 1, soluble [Homo sapiens]; (5749:) suppressor of variegation3-9 homolog 1 [Homo sapiens]; (5750:) SUR5 [Homo sapiens]; (5751:)Survivin; (5752:) SWI/SNF related, matrix associated, actin dependentregulator of chromatin, subfamily b, member 1 isoform a [Homo sapiens];(5753:) SWI/SNF related, matrix associated, actin dependent regulator ofchromatin, subfamily b, member 1 isoform b [Homo sapiens]; (5754:)SWI/SNF-related matrix-associated actin-dependent regulator of chromatina4 [Homo sapiens]; (5755:) SWI/SNF-related matrix-associatedactin-dependent regulator of chromatin a5 [Homo sapiens]; (5756:)synapsin I [Homo sapiens]; (5757:) synapsin I isoform Ia [Homo sapiens];(5758:) synapsin I isoform Ib [Homo sapiens]; (5759:) Synapsin-1(Synapsin I) (Brain protein 4.1); (5760:) synaptojanin 2 binding protein[Homo sapiens]; (5761:) synuclein alpha interacting protein [Homosapiens]; (5762:) synuclein, gamma (breast cancer-specific protein 1)[Homo sapiens]; (5763:) T cell receptor delta chain [Homo sapiens];(5764:) tachykinin receptor 1 isoform long [Homo sapiens]; (5765:)tachykinin receptor 1 isoform short [Homo sapiens]; (5766:) TAF2 protein[Homo sapiens]; (5767:) TAF9 RNA polymerase II isoform b [Homo sapiens];(5768:) TAF9 RNA polymerase II isoform c [Homo sapiens]; (5769:) TAF9RNA polymerase II, TATA box binding protein (TBP)-associated factor, 32kDa [Homo sapiens]; (5770:) talin 1 [Homo sapiens]; (5771:) TANK-bindingkinase 1 [Homo sapiens]; (5772:) tartrate resistant acid phosphatase 5precursor [Homo sapiens]; (5773:) Taste receptor type 1 member 1precursor (G-protein coupled receptor 70); (5774:) Taste receptor type 1member 2 precursor (G-protein coupled receptor 71) (Sweet taste receptorT1R2); (5775:) Taste receptor type 1 member 3 precursor (Sweet tastereceptor T1 R3); (5776:) Taste receptor type 2 member 1 (T2R1) (Tastereceptor family B member 7) (TRB7); (5777:) Taste receptor type 2 member10 (T2R10) (Taste receptor family B member 2) (TRB2); (5778:) Tastereceptor type 2 member 13 (T2R13) (Taste receptor family B member 3)(TRB3); (5779:) Taste receptor type 2 member 14 (T2R14) (Taste receptorfamily B member 1) (TRB1); (5780:) Taste receptor type 2 member 16(T2R16); (5781:) Taste receptor type 2 member 3 (T2R3); (5782:) Tastereceptor type 2 member 38 (T2R38) (T2R61) (PTC bitter taste receptor);(5783:) Taste receptor type 2 member 39 (T2R39) (T2R57); (5784:) Tastereceptor type 2 member 4 (T2R4); (5785:) Taste receptor type 2 member 40(T2R40) (T2R58) (G-protein coupled receptor 60); (5786:) Taste receptortype 2 member 41 (T2R41) (T2R59); (5787:) Taste receptor type 2 member42 (T2R42) (T2R55); (5788:) Taste receptor type 2 member 43 (T2R43)(T2R52); (5789:) Taste receptor type 2 member 44 (T2R44) (T2R53);(5790:) Taste receptor type 2 member 45 (T2R45) (G-protein coupledreceptor59); (5791:) Taste receptor type 2 member 46 (T2R46) (T2R54);(5792:) Taste receptor type 2 member 47 (T2R47); (5793:) Taste receptortype 2 member 48 (T2R48); (5794:) Taste receptor type 2 member 49(T2R49) (T2R56); (5795:) Taste receptor type 2 member 5 (T2R5); (5796:)Taste receptor type 2 member 50 (T2R50) (T2R51); (5797:) Taste receptortype 2 member 60 (T2R60) (T2R56); (5798:) Taste receptor type 2 member 7(T2R7) (Taste receptor family B member 4) (TRB4); (5799:) Taste receptortype 2 member 8 (T2R8) (Taste receptor family B member 5) (TRB5);(5800:) Taste receptor type 2 member 9 (T2R9) (Taste receptor family Bmember 6) (TRB6); (5801:) TBP-associated factor 1 isoform 1 [Homosapiens]; (5802:) TBP-associated factor 1 isoform 2 [Homo sapiens];(5803:) T-cell antigen CD7 precursor (GP40) (T-cell leukemia antigen)(TP41) (Leu-9); (5804:) T-cell receptor alpha chain (clone A21)—human(fragment); (5805:) T-cell receptor alpha chain (Mb11a) precursor—human(fragment); (5806:) T-cell receptor alpha chain C region; (5807:) T-cellreceptor alpha chain V region CTL-L17 precursor; (5808:) T-cell receptoralpha chain V region HPB-MLT precursor; (5809:) T-cell receptor alphachain V region PY14 precursor; (5810:) T-cell receptor beta chain Cregion; (5811:) T-cell receptor beta chain V region—human (fragment);(5812:) T-cell receptor beta chain V region CTL-L17 precursor; (5813:)T-cell receptor beta chain V region YT35 precursor; (5814:) T-cellreceptor gamma chain C region PT-gamma-1/2; (5815:) T-cell receptorgamma chain V region PT-gamma-1/2 precursor; (5816:) T-cell receptor VbCDR3, carrier PBL Vb 12a.sbt—human (fragment); (5817:) T-cell receptorVb CDR3, carrier PBL Vb 12b.sbt—human (fragment); (5818:) T-cellreceptor Vb CDR3, carrier PBL Vb 2.sbt—human (fragment); (5819:) T-cellreceptor Vb CDR3, carrier PBL Vb 6.sbt—human (fragment); (5820:) T-cellreceptor Vb CDR3, carrier PBL Vb 7.sbt—human (fragment); (5821:) T-cellreceptor Vb CDR3, carrier Vb 17.sbt—human (fragment); (5822:) T-cellreceptor Vb CDR3, Ctrl TCR Vb 12 CDR3aa.sbt—human (fragment); (5823:)T-cell receptor Vb CDR3, Ctrl TCR Vb 7CDR3aas.sbt—human (fragment);(5824:) T-cell receptor Vb CDR3, Ctrl TCR Vb8 CDR3aas.sbt—human(fragment); (5825:) T-cell receptor Vb CDR3, Ctr2 TCR Vb12CDR3aa.sbt—human (fragment); (5826:) T-cell receptor Vb CDR3, HAM1TCRVb12b CDR3a.sbt—human (fragment); (5827:) T-cell receptor Vb CDR3,HAM1TCR Vb14 CDR3a.sbt—human (fragment); (5828:) T-cell receptor VbCDR3, HAM1TCR Vb5a CDR3a.sbt—human (fragment); (5829:) T-cell receptorVb CDR3, HAM1TCR Vb5b CDR3a.sbt—human (fragment); (5830:) T-cellreceptor Vb CDR3, HAM1TCR Vb5C CDR3aa.sbt—human (fragment); (5831:)T-cell receptor Vb CDR3, HAM1TCR Vb5d CDR3a.sbt—human (fragment);(5832:) T-cell receptor Vb CDR3, HAM1TCR Vb6b CDR3a.sbt—human(fragment); (5833:) T-cell receptor Vb CDR3, HAM1TCR Vb7aCDR3a.sbt—human (fragment); (5834:) T-cell receptor Vb CDR3, HAM1TCRVb7b CDR3a.sbt—human (fragment); (5835:) T-cell receptor Vb CDR3,HAM1TCR Vb8a CDR3a.sbt—human (fragment); (5836:) T-cell receptor VbCDR3, HAMITCR Vb8b CDR3a.sbt—human (fragment); (5837:) T-cell receptorVb CDR3, HAM2TCR Vb 19a.sbt—human (fragment); (5838:) T-cell receptor VbCDR3, HAM2TCR Vb17 CDR3a.sbt—human (fragment); (5839:) T-cell receptorVb CDR3, HAM2TCR Vb19b CDR3a.sbt—human (fragment); (5840:) T-cellreceptor Vb CDR3, HAM2TCR Vb6a CDR3a.sbt—human (fragment); (5841:)T-cell receptor Vb CDR3, HAM2TCR Vb6b CDR3a.sbt—human (fragment);(5842:) T-cell receptor Vb CDR3, HAM2TCR Vb8a CDR3a.sbt—human(fragment); (5843:) T-cell receptor Vb CDR3, HAM2TCR Vb8cCDR3a.sbt—human (fragment); (5844:) T-cell receptor zeta chain isoform 1precursor [Homo sapiens]; (5845:) T-cell receptor zeta chain isoform 2precursor [Homo sapiens]; (5846:) T-cell surface glycoprotein CD3 deltachain precursor (T-cell receptor T3 delta chain); (5847:) T-cell surfaceglycoprotein CD3 epsilon chain precursor (T-cell surface antigenT3/Leu-4 epsilon chain); (5848:) T-cell surface glycoprotein CD3 gammachain precursor (T-cell receptor T3 gamma chain); (5849:) T-cell surfaceglycoprotein CD3 zeta chain precursor (T-cell receptor T3 zeta chain)(CD237 antigen); (5850:) T-cell, immune regulator 1 isoform a [Homosapiens]; (5851:) T-cell, immune regulator 1 isoform b [Homo sapiens];(5852:) TEA domain family member 3 [Homo sapiens]; (5853:) TEK ReceptorTyrosine Kinase Activator; (5854:) Telomerase; (5855:) TelomeraseActivator; (5856:) Telomerase reverse transcriptase (Telomerasecatalytic subunit) (HEST2) (Telomerase-associated protein 2) (TP2);(5857:) telomerase reverse transcriptase isoform 1 [Homo sapiens];(5858:) telomerase reverse transcriptase isoform 2 [Homo sapiens];(5859:) terminal deoxynucleotidyltransferase isoform 1 [Homo sapiens];(5860:) terminal deoxynucleotidyltransferase isoform 2 [Homo sapiens];(5861:) testicular ECA [Homo sapiens]; (5862:) testisin isoform 1 [Homosapiens]; (5863:) testisin isoform 2 [Homo sapiens]; (5864:) testisinisoform 3 [Homo sapiens]; (5865:) Testisin precursor (Eosinophil serineprotease 1) (ESP-1); (5866:) Testis-specific serine/threonine-proteinkinase 1 (TSSK-1) (Testis-specific kinase 1) (TSK-1)(Serine/threonine-protein kinase 22A); (5867:) Testis-specificserine/threonine-protein kinase 2 (TSSK-2) (Testis-specific kinase 2)(TSK-2) (Serine/threonine-protein kinase 22B) (DiGeorge syndrome proteinG); (5868:) Testis-specific serine/threonine-protein kinase 3 (TSSK-3)(Testis-specific kinase 3) (TSK-3) (Serine/threonine-protein kinase22C); (5869:) Testis-specific serine/threonine-protein kinase 4 (TSSK-4)(Testis-specific kinase 4) (TSK-4) (Serine/threonine-protein kinase22E); (5870:) TGF-beta receptor type III precursor (TGFR-3)(Transforming growth factor beta receptor III) (Betaglycan); (5871:)TGF-beta receptor type-1 precursor (TGF-beta receptor type I) (TGFR-1)(TGF-beta type I receptor) (Serine/threonine-protein kinase receptor R4)(SKR4) (Activin receptor-like kinase 5) (ALK-5); (5872:) TGF-betareceptor type-2 precursor (TGF-beta receptor type II) (TGFR-2) (TGF-betatype II receptor) (Transforming growth factor-beta receptor type II)(TbetaR-II); (5873:) The Solution Structure Of Reduced MonomericSuperoxide Dismutase, Nmr, 36 Structures; (5874:) thimet oligopeptidase1 [Homo sapiens]; (5875:) thioesterase 11 [Homo sapiens]; (5876:)Thiopurine S-methyltransferase (Thiopurine methyltransferase); (5877:)thiopurine S-methyltransferase [Homo sapiens]; (5878:) thioredoxin [Homosapiens]; (5879:) Thioredoxin domain-containing protein 2(Spermatid-specific thioredoxin-1) (Sptrx-1); (5880:) Thioredoxindomain-containing protein 6 (Thioredoxin-like protein2) (Txl-2); (5881:)thioredoxin peroxidase [Homo sapiens]; (5882:) Thioredoxin Reductase(TrxR); (5883:) thioredoxin reductase [Homo sapiens]; (5884:)thioredoxin reductase 1 [Homo sapiens]; (5885:) thioredoxin reductase 2precursor [Homo sapiens]; (5886:) Thioredoxin-1 (Trx-1); (5887:)Thioredoxin-dependent peroxide reductase, mitochondrial precursor(Peroxiredoxin-3) (PRX III) (Antioxidant protein 1) (AOP-1) (ProteinMER5 homolog) (HBC189); (5888:) thiosulfate sulfurtransferase [Homosapiens]; (5889:) Three prime repair exonuclease 1 (3′-5′ exonucleaseTREX1) (DNaseIII); (5890:) three prime repair exonuclease 1 isoform a[Homo sapiens]; (5891:) three prime repair exonuclease 1 isoform b [Homosapiens]; (5892:) three prime repair exonuclease 1 isoform c [Homosapiens]; (5893:) three prime repair exonuclease 1 isoform d [Homosapiens]; (5894:) three prime repair exonuclease 2 [Homo sapiens];(5895:) “Threonine aspartase 1 (Taspase-1) [Contains:) Threonineaspartase subunit alpha; Threonine aspartase subunit beta].”; (5896:)Threonine synthase-like 1 (bacterial) [Homo sapiens]; (5897:) threoninesynthase-like 1 [Homo sapiens]; (5898:) Threonine synthase-like 1;(5899:) Thrombin; (5900:) Thrombin Receptor; (5901:) Thrombomodulinprecursor (TM) (Fetomodulin) (CD141 antigen); (5902:) ThrombomodulinReceptor; (5903:) Thrombopoietin (TPO) Receptor; (5904:) Thrombopoietinreceptor precursor (TPO-R) (Myeloproliferative leukemia protein) (C-mpl)(CD110 antigen); (5905:) Thrombospondin-1 (TSP-1); (5906:) Thromboxane(TX) Synthesis; (5907:) thromboxane A synthase 1 (platelet, cytochromeP450, family 5, subfamily A) isoform TXS-I [Homo sapiens]; (5908:)thromboxane A synthase 1 (platelet, cytochrome P450, family 5, subfamilyA) isoform TXS-11 [Homo sapiens]; (5909:) Thromboxane A2 (TXA2)Receptor; (5910:) Thromboxane A2 receptor (TXA2-R) (Prostanoid TPreceptor); (5911:) thymidine kinase 1, soluble [Homo sapiens]; (5912:)thymidine kinase 2 [Homo sapiens]; (5913:) thymidine kinase 2,mitochondrial [Homo sapiens]; (5914:) Thymidine kinase 2, mitochondrialprecursor (Mt-TK); (5915:) Thymidine kinase, cytosolic; (5916:)Thymidine Phosphorylase (TP); (5917:) Thymidylate Synthase (TS); (5918:)thymidylate synthetase [Homo sapiens]; (5919:) thymine-DNA glycosylase[Homo sapiens]; (5920:) Thyroid Hormone Receptor (TR); (5921:) Thyroidhormone receptor alpha (C-erbA-alpha) (c-erbA-1) (EAR-7) (EAR7); (5922:)Thyroid hormone receptor beta-1; (5923:) Thyroid hormone receptorbeta-2; (5924:) Thyroid hormone receptor-associated protein 2 (Thyroidhormone receptor-associated protein complex 240 kDa component-like);(5925:) Thyroid hormone receptor-associated protein 3 (Thyroid hormonereceptor-associated protein complex 150 kDa component) (Trap150);(5926:) Thyroid hormone receptor-associated protein complex 240 kDacomponent (Trap240) (Thyroid hormone receptor-associated protein 1)(Vitamin D3 receptor-interacting protein complex component DRIP250)(DRIP 250) (Activator-recruited cofactor 250 kDa component) (ARC250);(5927:) Thyroid Hormone Receptor-Beta (TR Beta); (5928:) ThyroidPeroxidase; (5929:) thyroid peroxidase [Homo sapiens]; (5930:) thyroidperoxidase isoform a [Homo sapiens]; (5931:) thyroid peroxidase isoformb [Homo sapiens]; (5932:) thyroid peroxidase isoform c [Homo sapiens];(5933:) thyroid peroxidase isoform d [Homo sapiens]; (5934:) thyroidperoxidase isoform e [Homo sapiens]; (5935:) Thyroid peroxidaseprecursor (TPO); (5936:) Thyroid receptor-interacting protein 12(TRIP12); (5937:) Thyrotropin receptor precursor (TSH-R)(Thyroid-stimulating hormone receptor); (5938:) Thyrotropin-ReleasingHormone (TRH) Receptor; (5939:) thyrotropin-releasing hormone degradingenzyme [Homo sapiens]; (5940:) Thyrotropin-releasing hormone receptor(TRH-R) (Thyroliberin receptor); (5941:) Tie-1 Receptor Tyrosine Kinase;(5942:) TIGD5 protein [Homo sapiens]; (5943:) Tissue alpha-L-fucosidaseprecursor (Alpha-L-fucosidase I) (Alpha-L-fucoside fucohydrolase);(5944:) Tissue Factor; (5945:) tissue inhibitor of metalloproteinase 1precursor [Homo sapiens]; (5946:) tissue inhibitor of metalloproteinase2 precursor [Homo sapiens]; (5947:) tissue inhibitor ofmetalloproteinase 3 precursor [Homo sapiens]; (5948:) tissue inhibitorof metalloproteinase 4 precursor [Homo sapiens]; (5949:) tissuenon-specific alkaline phosphatase precursor [Homo sapiens]; (5950:)Tissue Plasminogen Activator (tPA); (5951:) tissue plasminogen activator(t-PA) [Homo sapiens]; (5952:) “Tissue-type plasminogen activatorprecursor (tPA) (t-PA) (t-plasminogen activator) (Alteplase) (Reteplase)[Contains:Tissue-type plasminogen activator chain A; Tissue-typeplasminogen activator chain B].”; (5953:) Titin (Connectin)(Rhabdomyosarcoma antigen MU-RMS-40.14); (5954:) TLL1 protein [Homosapiens]; (5955:) TLL2 protein [Homo sapiens]; (5956:) T-lymphocyteactivation antigen CD80 precursor (Activation B7-1 antigen) (CTLA-4counter-receptor B7.1) (B7) (BB1); (5957:) T-lymphocyte activationantigen CD86 precursor (Activation B7-2antigen) (CTLA-4 counter-receptorB7.2) (B70) (FUN-1) (BU63); (5958:) T-lymphokine-activated killercell-originated protein kinase (T-LAK cell-originated protein kinase)(PDZ-binding kinase) (Spermatogenesis-related protein kinase) (SPK)(MAPKK-like protein kinase) (Nori-3); (5959:) TNF receptor-associatedfactor 2 (Tumor necrosis factor type 2receptor-associated protein 3);(5960:) TNF receptor-associated factor 6 (Interleukin 1 signaltransducer) (RING finger protein 85); (5961:) TNF receptor-associatedfactor 6 [Homo sapiens]; (5962:) TNF-alpha converting enzyme [Homosapiens]; (5963:) TNF-alpha converting enzyme precursor [Homo sapiens];(5964:) Toll-Like Receptor (TLR); (5965:) Toll-like receptor 1 precursor(Toll/interleukin-1 receptor-like protein) (TIL) (CD281 antigen);(5966:) Toll-like receptor 10 precursor (CD290 antigen); (5967:)Toll-like receptor 2 precursor (Toll/interleukin 1 receptor-like protein4) (CD282 antigen); (5968:) Toll-Like Receptor 3 (TLR3); (5969:)Toll-like receptor 3 precursor (CD283 antigen); (5970:) Toll-LikeReceptor 4 (TLR4); (5971:) Toll-like receptor 4 precursor (hToll) (CD284antigen); (5972:) toll-like receptor 4 precursor [Homo sapiens]; (5973:)Toll-like receptor 5 precursor (Toll/interleukin-1 receptor-like protein3); (5974:) Toll-like receptor 6 precursor; (5975:) Toll-Like Receptor 7(TLR7); (5976:) Toll-like receptor 7 precursor; (5977:) Toll-likereceptor 8 precursor (CD288 antigen); (5978:) Toll-Like Receptor 9(TLR9); (5979:) Toll-like receptor 9 precursor (CD289 antigen); (5980:)topoisomerase (DNA) III alpha [Homo sapiens]; (5981:) topoisomerase(DNA) III beta [Homo sapiens]; (5982:) Topoisomerase I; (5983:)Topoisomerase II; (5984:) Topoisomerase IV; (5985:)topoisomerase-related function protein [Homo sapiens]; (5986:)TP53-induced glycolysis and apoptosis regulator [Homo sapiens]; (5987:)TPA:) ubiquitin-specific protease 17-like protein [Homo sapiens];(5988:) TPA-exp:) cytosolic 5′(3′)-deoxyribonucleotidase [Homo sapiens];(5989:) TPK1 protein [Homo sapiens]; (5990:) Trace amine-associatedreceptor 1 (Trace amine receptor 1) (TaR-1); (5991:) Traceamine-associated receptor 2 (G-protein coupled receptor 58); (5992:)Trace amine-associated receptor 3 (G-protein coupled receptor 57);(5993:) Trace amine-associated receptor 5 (Putative neurotransmitterreceptor); (5994:) Trace amine-associated receptor 6 (Trace aminereceptor 4) (TaR-4); (5995:) Trace amine-associated receptor 8 (Traceamine receptor 5) (TaR-5) (G-protein coupled receptor 102); (5996:)Trace amine-associated receptor 9 (Trace amine receptor 3) (TaR-3);(5997:) TRAF6-regulated IKK activator 1 beta Uev1A [Homo sapiens];(5998:) Trans-2-enoyl-CoA reductase, mitochondrial precursor (HsNrbf-1)(NRBF-1); (5999:) transacylase [Homo sapiens]; (6000:) transaldolase 1[Homo sapiens]; (6001:) Transcription elongation factor B (SIII),polypeptide 2 (18 kDa, elongin B) [Homo sapiens]; (6002:) Transcriptionelongation factor B polypeptide 2 (RNA polymerase II transcriptionfactor SIII subunit B) (SIII p18) (Elongin B) (EloB) (Elongin 18 kDasubunit); (6003:) Transcription elongation factor SPT4 (hSPT4) (DRBsensitivity-inducing factor small subunit) (DSIF small subunit) (DSIFp14); (6004:) Transcription elongation factor SPT5 (hSPT5) (DRBsensitivity-inducing factor large subunit) (DSIF large subunit) (DSIFp160) (Tat-cotransactivator 1 protein) (Tat-CT1 protein); (6005:)transcription factor 1, hepatic [Homo sapiens]; (6006:) transcriptionfactor AP-2 alpha isoform a [Homo sapiens]; (6007:) transcription factorAP-2 alpha isoform b [Homo sapiens]; (6008:) transcription factor AP-2alpha isoform c [Homo sapiens]; (6009:) transcription factor AP-2 beta(activating enhancer binding protein2 beta) [Homo sapiens]; (6010:)transcription factor AP-2 gamma [Homo sapiens]; (6011:) Transcriptionfactor CP2-like protein 1 (CP2-related transcriptional repressor 1)(CRTR-1) (Transcription factor LBP-9); (6012:) transcription factorLBP-1b [Homo sapiens]; (6013:) transcription factor LBP-9 [Homosapiens]; (6014:) Transcription factor p65 (Nuclear factor NF-kappa-Bp65 subunit); (6015:) transcription factor-like protein 4 isoform alpha[Homo sapiens]; (6016:) transcription factor-like protein 4 isoform beta[Homo sapiens]; (6017:) transcription factor-like protein 4 isoformgamma [Homo sapiens]; (6018:) Transcription initiation factor IIF alphasubunit (TFIIF-alpha) (Transcription initiation factor RAP74) (Generaltranscription factor IIF polypeptide 174 kDa subunit protein); (6019:)Transcription initiation factor TFIID subunit 1 (Transcriptioninitiation factor TFIID 250 kDa subunit) (TAF(II)250) (TAFII-250)(TAFI1250) (TBP-associated factor 250 kDa) (p250) (Cell cycle gene 1protein); (6020:) Transcriptional repressor NF-XI (Nuclear transcriptionfactor, Xbox-binding, 1); (6021:) transferrin [Homo sapiens]; (6022:)Transferrin Receptor (Tf-R); (6023:) Transferrin receptor protein 1(TfR1) (TR) (TfR) (Trfr) (CD71 antigen) (T9) (p90); (6024:) Transferrinreceptor protein 2 (TfR2); (6025:) Transforming growth factor-beta(TGF-beta); (6026:) Transforming growth factor-beta 1 (TGF-beta 1);(6027:) Transforming growth factor-beta 2 (TGF-beta 2); (6028:)Transforming growth factor alpha (TGF-alpha); (6029:) transforminggrowth factor, alpha [Homo sapiens]; (6030:) transforming growth factor,beta 1 [Homo sapiens]; (6031:) transforming growth factor, beta receptor11 isoform A precursor[Homo sapiens]; (6032:) transforming growthfactor, beta receptor 11 isoform B precursor[Homo sapiens]; (6033:)Transforming Growth Factor-Beta3 (TGF-Beta3) Receptor; (6034:)Transglutaminase (TGase); (6035:) transglutaminase 1 [Homo sapiens];(6036:) transglutaminase 2 isoform a [Homo sapiens]; (6037:)transglutaminase 2 isoform b [Homo sapiens]; (6038:) transglutaminase 3precursor [Homo sapiens]; (6039:) transglutaminase K enzyme; (6040:)Transient receptor potential cation channel subfamily M member 2(Longtransient receptor potential channel 2) (LTrpC2) (LTrpC-2) (Transientreceptor potential channel 7) (TrpC7) (Estrogen-responsiveelement-associated gene 1 protein); (6041:) Transketolase (TK); (6042:)transketolase-like 1 [Homo sapiens]; (6043:) translation repressor NAT1[Homo sapiens]; (6044:) transmembrane 4 superfamily member 15 [Homosapiens]; (6045:) transmembrane aspartic proteinase Asp 1 [Homosapiens]; (6046:) transmembrane aspartic proteinase Asp 2 [Homosapiens]; (6047:) Transmembrane glycoprotein NMB precursor(Transmembrane glycoprotein HGFIN); (6048:) transmembrane protease,serine 11 D [Homo sapiens]; (6049:) “Transmembrane protease, serine 11 Dprecursor (Airway trypsin-like protease) [Contains:) Transmembraneprotease, serine 11 D non-catalytic chain; Transmembrane protease,serine 11D catalytic chain].”; (6050:) Transmembrane protease, serine 13(Mosaic serine protease) (Membrane-type mosaic serine protease); (6051:)transmembrane protease, serine 13 [Homo sapiens]; (6052:) “Transmembraneprotease, serine 9 (Polyserase-1) (Polyserase-1) (Polyserine protease 1)[Contains:) Serase-1; Serase-2; Serase-3].”; (6053:) trehalase [Homosapiens]; (6054:) Trem-like transcript 1 protein precursor (TLT-1)(Triggering receptor expressed on myeloid cells-like protein 1); (6055:)Trem-like transcript 2 protein precursor (TLT-2) (Triggering receptorexpressed on myeloid cells-like protein 2); (6056:) TRIAD3 proteinisoform a [Homo sapiens]; (6057:) TRIAD3 protein isoform b [Homosapiens]; (6058:) “Trifunctional enzyme subunit alpha, mitochondrialprecursor (TP-alpha) (78 kDa gastrin-binding protein) [Includes:)Long-chain enoyl-CoA hydratase; Long chain 3-hydroxyacyl-CoAdehydrogenase].”; (6059:) Trifunctional enzyme subunit beta,mitochondrial precursor (TP-beta) [Includes:) 3-ketoacyl-CoA thiolase(Acetyl-CoA acyltransferase) (Beta-ketothiolase)]; (6060:) Triggeringreceptor expressed on myeloid cells 1 precursor (TREM-1) (Triggeringreceptor expressed on monocytes 1); (6061:) Triggering receptorexpressed on myeloid cells 2 precursor (Triggering receptor expressed onmonocytes 2) (TREM-2); (6062:) Triggering Receptor Expressed on MyeloidCells-1 (TREM-1) Receptor; (6063:) Trimethyllysine dioxygenase,mitochondrial precursor (Epsilon-trimethyllysine 2-oxoglutaratedioxygenase) (TML-alpha-ketoglutarate dioxygenase) (TML hydroxylase)(TML dioxygenase) (TMLD); (6064:) trimethyllysine hydroxylase, epsilon[Homo sapiens]; (6065:) Triosephosphate isomerase (TIM)(Triose-phosphate isomerase); (6066:) triosephosphate isomerase 1 [Homosapiens]; (6067:) tripeptidyl peptidase 11 [Homo sapiens]; (6068:)tripeptidyl peptidase II; (6069:) Tripeptidyl-peptidase 2(Tripeptidyl-peptidase II) (TPP-II) (Tripeptidyl aminopeptidase);(6070:) tripeptidyl-peptidase I precursor [Homo sapiens]; (6071:) tRNA5-methylaminomethyl-2-thiouridylate methyltransferase 1 [Homo sapiens];(6072:) tRNA isopentenyl transferase [Homo sapiens]; (6073:) tRNAisopentenyltransferase 1 [Homo sapiens]; (6074:) tRNAisopentenyltransferase, mitochondrial precursor(Isopentenyl-diphosphate:tRNA isopentenyltransferase) (IPP transferase)(IPTase) (IPPT) (hGRO1); (6075:) tRNA nucleotidyl transferase,CCA-adding, 1 isoform 1 [Homo sapiens]; (6076:) tRNA nucleotidyltransferase, CCA-adding, 1 isoform 2 [Homo sapiens]; (6077:)tRNA-guanine transglycosylase [Homo sapiens]; (6078:)tRNA-nucleotidyltransferase [Homo sapiens]; (6079:)tRNA-nucleotidyltransferase 1, mitochondrial precursor (MitochondrialtRNA nucleotidyl transferase, CCA-adding) (mt tRNA adenylyltransferase)(mt tRNA CCA-pyrophosphorylase) (mt tRNACCA-diphosphorylase) (mtCCA-adding enzyme); (6080:) truncated mercaptopyruvate sulfurtransferasevariant [Homo sapiens]; (6081:) Trypanosoma Cruzi TrypanothioneReductase; (6082:) Trypsin; (6083:) Tryptase; (6084:) Tryptase Beta;(6085:) Tryptase delta precursor (Delta tryptase) (Mast cellmMCP-7-like) (Tryptase-3) (HmMCP-3-like tryptase I11); (6086:)tryptophan hydroxylase 1 [Homo sapiens]; (6087:) tryptophanyl-tRNAsynthetase isoform a [Homo sapiens]; (6088:) tryptophanyl-tRNAsynthetase isoform b [Homo sapiens]; (6089:) TTLL3 protein [Homosapiens]; (6090:) T-Type Calcium Channel (CaV3.1d) Blocker; (6091:)Tubulin; (6092:) Tubulin Polymerase; (6093:) tubulin tyrosine ligase[Homo sapiens]; (6094:) Tumor Necrosis Apoptosis Inducing LigandReceptor 1 (TRAIL-R1); (6095:) Tumor Necrosis Apoptosis Inducing LigandReceptor 2 (TRAIL-R2); (6096:) Tumor Necrosis Factor (TNF) Release;(6097:) tumor necrosis factor alpha [Homo sapiens]; (6098:) “Tumornecrosis factor ligand superfamily member 11 (Receptor activator ofnuclear factor kappa B ligand) (RANKL) (TNF-related activation-inducedcytokine) (TRANCE) (Osteoprotegerin ligand) (OPGL) (Osteoclastdifferentiation factor) (ODF) (CD254 antigen)[Contains:) Tumor necrosisfactor ligand superfamily member 11, membrane form; Tumor necrosisfactor ligand superfamily member 11, soluble form].”; (6099:) tumornecrosis factor ligand superfamily, member 11 isoform 1 [Homo sapiens];(6100:) tumor necrosis factor ligand superfamily, member 11 isoform 2[Homo sapiens]; (6101:) Tumor Necrosis Factor Receptor 1 (TNFR1);(6102:) tumor necrosis factor receptor 1 precursor [Homo sapiens];(6103:) Tumor necrosis factor receptor superfamily member 10A precursor(Death receptor 4) (TNF-related apoptosis-inducing ligand receptors)(TRAIL receptor 1) (TRAIL-R1) (CD261 antigen); (6104:) Tumor necrosisfactor receptor superfamily member 10B precursor (Death receptor 5)(TNF-related apoptosis-inducing ligand receptor2) (TRAIL receptor 2)(TRAIL-R2) (CD262 antigen); (6105:) Tumor necrosis factor receptorsuperfamily member 10C precursor (Decoy receptor 1) (DcR1) (Decoy TRAILreceptor without death domain) (TNF-related apoptosis-inducing ligandreceptor 3) (TRAIL receptor 3) (TRAIL-R3) (Trail receptor without anintracellular domain) (Lymphocyte inhibitor of TRAIL) (Antagonist decoyreceptor for TRAIL/Apo-2L) (CD263 antigen); (6106:) Tumor necrosisfactor receptor superfamily member 10D precursor (Decoy receptor 2)(DcR2) (TNF-related apoptosis-inducing ligand receptor 4) (TRAILreceptor 4) (TRAIL-R4) (TRAIL receptor with a truncated death domain)(CD264 antigen); (6107:) Tumor necrosis factor receptor superfamilymember 11A precursor (Receptor activator of NF-KB) (Osteoclastdifferentiation factor receptor) (ODFR) (CD265 antigen); (6108:) Tumornecrosis factor receptor superfamily member 11B precursor(Osteoprotegerin) (Osteoclastogenesis inhibitory factor); (6109:) Tumornecrosis factor receptor superfamily member 12A precursor (Fibroblastgrowth factor-inducible immediate-early response protein 14)(FGF-inducible 14) (Tweak-receptor) (TweakR) (CD266antigen); (6110:)Tumor necrosis factor receptor superfamily member 13B(Transmembraneactivator and CAML interactor) (CD267 antigen); (6111:) Tumor necrosisfactor receptor superfamily member 13C (B cell-activating factorreceptor) (BAFF receptor) (BAFF-R) (BLyS receptor 3) (CD268 antigen);(6112:) Tumor necrosis factor receptor superfamily member 14 precursor(Herpesvirus entry mediator A) (Tumor necrosis factor receptor-like2)(TR2); (6113:) Tumor necrosis factor receptor superfamily member 16precursor (Low-affinity nerve growth factor receptor) (NGF receptor)(Gp80-LNGFR) (p75 ICD) (Low affinity neurotrophin receptor p75NTR)(CD271 antigen); (6114:) Tumor necrosis factor receptor superfamilymember 17 (B-cell maturation protein) (CD269 antigen); (6115:) Tumornecrosis factor receptor superfamily member 18 precursor(Glucocorticoid-induced TNFR-related protein) (Activation-inducible TNFR family receptor); (6116:) Tumor necrosis factor receptor superfamilymember 19 precursor (Toxicity and JNK inducer) (TRADE); (6117:) Tumornecrosis factor receptor superfamily member 19L precursor (Receptorexpressed in lymphoid tissues); (6118:) “Tumor necrosis factor receptorsuperfamily member 1A precursor (p60) (TNF-R1) (TNF-R1) (TNFR-1) (p55)(CD120a antigen) [Contains:Tumor necrosis factor receptor superfamilymember 1A, membrane form; Tumor necrosis factor-binding protein 1(TBPI)].”; (6119:) “Tumor necrosis factor receptor superfamily member 1Bprecursor (Tumor necrosis factor receptor 2) (TNF-R2) (Tumor necrosisfactor receptor type II) (p75) (p80 TNF-alpha receptor) (CD120b antigen)(Etanercept) [Contains:) Tumor necrosis factor receptor superfamilymember 1b, membrane form; Tumor necrosis factor-binding protein 2(TBP11)(TBP-2)].”; (6120:) Tumor necrosis factor receptor superfamily member 21precursor (TNFR-related death receptor 6) (Death receptor 6); (6121:)Tumor necrosis factor receptor superfamily member 25 precursor (WSL-1protein) (Apoptosis-mediating receptor DR3) (Apoptosis-mediatingreceptor TRAMP) (Death domain receptor 3) (WSL protein)(Apoptosis-inducing receptor AIR) (Apo-3) (Lymphocyte-associatedreceptor of death) (LARD); (6122:) Tumor necrosis factor receptorsuperfamily member 27 (X-linked ectodysplasin-A2 receptor) (EDA-A2receptor); (6123:) Tumor necrosis factor receptor superfamily member 3precursor (Lymphotoxin-beta receptor) (Tumor necrosis factorreceptor2-related protein) (Tumor necrosis factor C receptor); (6124:)Tumor necrosis factor receptor superfamily member 4 precursor (OX40Lreceptor) (ACT35 antigen) (TAX transcriptionally-activated glycoprotein1 receptor) (CD134 antigen); (6125:) Tumor necrosis factor receptorsuperfamily member 5 precursor (CD40L receptor) (B-cell surface antigenCD40) (CDw40) (Bp50); (6126:) Tumor necrosis factor receptor superfamilymember 6 precursor (FASLG receptor) (Apoptosis-mediating surface antigenFAS) (Apo-1 antigen) (CD95 antigen); (6127:) Tumor necrosis factorreceptor superfamily member 6B precursor (Decoy receptor for Fas ligand)(Decoy receptor 3) (DcR3) (M68); (6128:) Tumor necrosis factor receptorsuperfamily member 7 precursor (CD27L receptor) (T-cell activationantigen CD27) (T14); (6129:) Tumor necrosis factor receptor superfamilymember 8 precursor (CD30L receptor) (Lymphocyte activation antigen CD30)(KI-1 antigen); (6130:) Tumor necrosis factor receptor superfamilymember 9 precursor (4-1BB ligand receptor) (T-cell antigen 4-1BBhomolog) (T-cell antigen ILA) (CD137 antigen) (CDw137); (6131:) Tumornecrosis factor receptor superfamily member EDAR precursor (Anhidroticectodysplasin receptor 1) (Ectodysplasin-A receptor) (EDA-A1 receptor)(Ectodermal dysplasia receptor) (Downless homolog); (6132:) tumornecrosis factor receptor superfamily, member 6 isoform 1precursor [Homosapiens]; (6133:) tumor necrosis factor receptor superfamily, member 6isoform 2precursor [Homo sapiens]; (6134:) tumor necrosis factorreceptor superfamily, member 6 isoform 3precursor [Homo sapiens];(6135:) tumor necrosis factor receptor superfamily, member 6 isoform4precursor [Homo sapiens]; (6136:) tumor necrosis factor receptorsuperfamily, member 6 isoform 5precursor [Homo sapiens]; (6137:) tumornecrosis factor receptor superfamily, member 6 isoform 6precursor [Homosapiens]; (6138:) tumor necrosis factor receptor superfamily, member 6isoform 7precursor [Homo sapiens]; (6139:) tumor necrosis factorreceptor superfamily, member 8 isoform 1 precursor [Homo sapiens];(6140:) tumor necrosis factor receptor superfamily, member 8 isoform 2[Homo sapiens]; (6141:) tumor necrosis factor, alpha-induced protein 8isoform a [Homo sapiens]; (6142:) tumor necrosis factor, alpha-inducedprotein 8 isoform b [Homo sapiens]; (6143:) Tumor Necrosis Factor-Alpha(TNF-Alpha) Synthesis; (6144:) Tumor Necrosis Factor-Alpha ConvertingEnzyme (TACE); (6145:) tumor protein p53 [Homo sapiens]; (6146:) tumorstroma and activated macrophage protein DLM-1 [Homo sapiens]; (6147:)Tumor susceptibility gene 101 protein; (6148:) “Tumor-associatedhydroquinone oxidase (tNOX) (Cytosolic ovarian carcinoma antigen 1)(APK1 antigen) [Includes:) Hydroquinone [NADH]oxidase; Proteindisulfide-thiol oxidoreductase].”; (6149:) Tumour Cell SurvivalPhosphatase-1 (TCSP-1); (6150:) TX protease precursor [Homo sapiens];(6151:) TY protease [Homo sapiens]; (6152:) Type IIinositol-3,4-bisphosphate 4-phosphatase (Inositol polyphosphate4-phosphatase type II); (6153:) Type-1 angiotensin II receptor (AT1)(AT1AR) (AT1 BR); (6154:) Type-2 angiotensin II receptor (AT2); (6155:)Tyrosinase; (6156:) Tyrosinase precursor (Monophenol monooxygenase)(Tumor rejection antigen AB) (SK29-AB) (LB24-AB); (6157:) tyrosinaseprecursor [Homo sapiens]; (6158:) tyrosine 3/tryptophan 5-monooxygenaseactivation protein, thetapolypeptide [Homo sapiens]; (6159:) tyrosine3/tryptophan 5-monooxygenase activation protein, zetapolypeptide [Homosapiens]; (6160:) Tyrosine 3-monooxygenase (Tyrosine 3-hydroxylase)(TH); (6161:) tyrosine hydroxylase isoform a [Homo sapiens]; (6162:)tyrosine hydroxylase isoform b [Homo sapiens]; (6163:) tyrosinehydroxylase isoform c [Homo sapiens]; (6164:) Tyrosine Kinase; (6165:)Tyrosine-protein kinase 6 (Breast tumor kinase) (Tyrosine-protein kinaseBRK); (6166:) Tyrosine-protein kinase receptor Tie-1 precursor; (6167:)Tyrosine-protein kinase receptor TYRO3 precursor (Tyrosine-proteinkinase RSE) (Tyrosine-protein kinase SKY) (Tyrosine-protein kinase DTK)(Protein-tyrosine kinase byk); (6168:) Tyrosine-protein kinase receptorUFO precursor (AXL oncogene); (6169:) Tyrosine-protein kinase RYKprecursor; (6170:) Tyrosine-protein kinase transmembrane receptor ROR1precursor (Neurotrophic tyrosine kinase, receptor-related 1); (6171:)Tyrosine-protein kinase transmembrane receptor ROR2 precursor(Neurotrophic tyrosine kinase, receptor-related 2); (6172:)Tyrosine-protein kinase-like 7 precursor (Colon carcinoma kinase 4)(CCK-4); (6173:) Tyrosine-protein phosphatase non-receptor type II(Protein-tyrosine phosphatase 2C) (PTP-2C) (PTP-1 D) (SH-PTP3) (SH-PTP2)(SHP-2) (Shp2); (6174:) Tyrosyl-DNA phosphodiesterase 1 (Tyr-DNAphosphodiesterase 1); (6175:) tyrosyl-DNA phosphodiesterase 1 [Homosapiens]; (6176:) tyrosyl protein sulfotransferase 1 [Homo sapiens];(6177:) tyrosyl protein sulfotransferase-1 [Homo sapiens]; (6178:)tyrosyl protein sulfotransferase-2 [Homo sapiens]; (6179:) “tyrosylprotein sulfotransferase-2; TPST-2 [Homo sapiens].”; (6180:)tyrosyl-tRNA synthetase [Homo sapiens]; (6181:) UBA2 [Homo sapiens];(6182:) UBA3 [Homo sapiens]; (6183:) UBC13/UEV-interacting ring fingerprotein [Homo sapiens]; (6184:) Ubc6p homolog [Homo sapiens]; (6185:)UbCH5B; (6186:) UbCH5C; (6187:) UbcM2 [Homo sapiens]; (6188:) UBE1C[Homo sapiens]; (6189:) UBE1L protein [Homo sapiens]; (6190:) UBE1L2protein [Homo sapiens]; (6191:) UBE21 [Homo sapiens]; (6192:) UBE2B[Homo sapiens]; (6193:) UBE2C [Homo sapiens]; (6194:) UBE2D3 [Homosapiens]; (6195:) UBE2G1 protein [Homo sapiens]; (6196:) UBE2H protein[Homo sapiens]; (6197:) UBE21 protein [Homo sapiens]; (6198:) UBE2L3[Homo sapiens]; (6199:) UBE2L6 [Homo sapiens]; (6200:) UBE20 protein[Homo sapiens]; (6201:) UBE2Q [Homo sapiens]; (6202:) UBE2Q1 protein[Homo sapiens]; (6203:) UBE2Q2 protein [Homo sapiens]; (6204:) UBE2R2[Homo sapiens]; (6205:) UBE2S protein [Homo sapiens]; (6206:) UBE2V1protein [Homo sapiens]; (6207:) UBE2V2 [Homo sapiens]; (6208:) UBE2Wprotein [Homo sapiens]; (6209:) UBE2Z protein [Homo sapiens]; (6210:)ubenimex (Bestatin)-sensitive aminopeptidase B-like enzyme(EC3.4.11.-)—human (fragments); (6211:) ubiquinol-cytochrome-c reductase(EC 1.10.2.2) cytochrome b—human mitochondrion; (6212:) Ubiquitinactivating enzyme [Homo sapiens]; (6213:) ubiquitin activating enzyme E1[Homo sapiens]; (6214:) ubiquitin associated protein 2 [Homo sapiens];(6215:) ubiquitin B precursor [Homo sapiens]; (6216:) ubiquitincarboxyl-terminal esterase L1 (ubiquitin thiolesterase) [Homo sapiens];(6217:) ubiquitin carboxyl-terminal esterase L3 [Homo sapiens]; (6218:)Ubiquitin carboxyl-terminal hydrolase 1 (Ubiquitin thioesterase 1)(Ubiquitin-specific-processing protease 1) (Deubiquitinating enzyme 1)(hUBP); (6219:) Ubiquitin carboxyl-terminal hydrolase 10 (Ubiquitinthioesterase 10) (Ubiquitin-specific-processing protease 10)(Deubiquitinating enzyme 10); (6220:) Ubiquitin carboxyl-terminalhydrolase 11 (Ubiquitin thioesterase 11) (Ubiquitin-specific-processingprotease 11) (Deubiquitinating enzyme 11); (6221:) Ubiquitincarboxyl-terminal hydrolase 12 (Ubiquitin thioesterase 12)(Ubiquitin-specific-processing protease 12) (Deubiquitinating enzyme 12)(Ubiquitin-hydrolyzing enzyme 1); (6222:) Ubiquitin carboxyl-terminalhydrolase 13 (Ubiquitin thioesterase 13) (Ubiquitin-specific-processingprotease 13) (Deubiquitinating enzyme 13) (Isopeptidase T-3) (ISOT-3);(6223:) Ubiquitin carboxyl-terminal hydrolase 14 (Ubiquitin thioesterase14) (Ubiquitin-specific-processing protease 14) (Deubiquitinating enzyme14); (6224:) Ubiquitin carboxyl-terminal hydrolase 15 (Ubiquitinthioesterase 15) (Ubiquitin-specific-processing protease 15)(Deubiquitinating enzyme 15) (Unph-2) (Unph4); (6225:) Ubiquitincarboxyl-terminal hydrolase 16 (Ubiquitin thioesterase 16)(Ubiquitin-specific-processing protease 16) (Deubiquitinating enzyme 16)(Ubiquitin-processing protease UBP-M); (6226:) Ubiquitincarboxyl-terminal hydrolase 17-like protein (Ubiquitinthioesterase17-like) (Ubiquitin-specific-processing protease 17-like)(Deubiquitinating enzyme 17-like); (6227:) Ubiquitin carboxyl-terminalhydrolase 19 (Ubiquitin thioesterase 19) (Ubiquitin-specific-processingprotease 19) (Deubiquitinating enzyme 19) (Zinc finger MYNDdomain-containing protein 9); (6228:) Ubiquitin carboxyl-terminalhydrolase 2 (Ubiquitin thioesterase 2) (Ubiquitin-specific-processingprotease 2) (Deubiquitinating enzyme2) (41 kDa ubiquitin-specificprotease); (6229:) Ubiquitin carboxyl-terminal hydrolase 20 (Ubiquitinthioesterase 20) (Ubiquitin-specific-processing protease 20)(Deubiquitinating enzyme 20); (6230:) Ubiquitin carboxyl-terminalhydrolase 21 (Ubiquitin thioesterase 21) (Ubiquitin-specific-processingprotease 21) (Deubiquitinating enzyme 21) (NEDD8-specific protease);(6231:) Ubiquitin carboxyl-terminal hydrolase 22 (Ubiquitin thioesterase22) (Ubiquitin-specific-processing protease 22) (Deubiquitinating enzyme22); (6232:) Ubiquitin carboxyl-terminal hydrolase 24 (Ubiquitinthioesterase 24) (Ubiquitin-specific-processing protease 24)(Deubiquitinating enzyme 24); (6233:) Ubiquitin carboxyl-terminalhydrolase 25 (Ubiquitin thioesterase 25) (Ubiquitin-specific-processingprotease 25) (Deubiquitinating enzyme 25) (USP on chromosome 21);(6234:) Ubiquitin carboxyl-terminal hydrolase 26 (Ubiquitin thioesterase26) (Ubiquitin-specific-processing protease 26) (Deubiquitinating enzyme26); (6235:) Ubiquitin carboxyl-terminal hydrolase 28 (Ubiquitinthioesterase 28) (Ubiquitin-specific-processing protease 28)(Deubiquitinating enzyme 28); (6236:) Ubiquitin carboxyl-terminalhydrolase 29 (Ubiquitin thioesterase 29) (Ubiquitin-specific-processingprotease 29) (Deubiquitinating enzyme 29); (6237:) Ubiquitincarboxyl-terminal hydrolase 3 (Ubiquitin thioesterase 3)(Ubiquitin-specific-processing protease 3) (Deubiquitinating enzyme3);(6238:) Ubiquitin carboxyl-terminal hydrolase 30 (Ubiquitin thioesterase30) (Ubiquitin-specific-processing protease 30) (Deubiquitinating enzyme30); (6239:) Ubiquitin carboxyl-terminal hydrolase 31 (Ubiquitinthioesterase 31) (Ubiquitin-specific-processing protease 31)(Deubiquitinating enzyme 31); (6240:) Ubiquitin carboxyl-terminalhydrolase 32 (Ubiquitin thioesterase 32) (Ubiquitin-specific-processingprotease 32) (Deubiquitinating enzyme 32) (NY-REN-60 antigen); (6241:)Ubiquitin carboxyl-terminal hydrolase 33 (Ubiquitin thioesterase 33)(Ubiquitin-specific-processing protease 33) (Deubiquitinating enzyme 33)(VHL-interacting deubiquitinating enzyme 1); (6242:) Ubiquitincarboxyl-terminal hydrolase 34 (Ubiquitin thioesterase 34)(Ubiquitin-specific-processing protease 34) (Deubiquitinating enzyme34); (6243:) Ubiquitin carboxyl-terminal hydrolase 35 (Ubiquitinthioesterase 35) (Ubiquitin-specific-processing protease 35)(Deubiquitinating enzyme 35); (6244:) Ubiquitin carboxyl-terminalhydrolase 36 (Ubiquitin thioesterase 36) (Ubiquitin-specific-processingprotease 36) (Deubiquitinating enzyme 36); (6245:) Ubiquitincarboxyl-terminal hydrolase 37 (Ubiquitin thioesterase 37)(Ubiquitin-specific-processing protease 37) (Deubiquitinating enzyme37); (6246:) Ubiquitin carboxyl-terminal hydrolase 38 (Ubiquitinthioesterase 38) (Ubiquitin-specific-processing protease 38)(Deubiquitinating enzyme 38) (HP43.8 KD); (6247:) Ubiquitincarboxyl-terminal hydrolase 4 (Ubiquitin thioesterase 4)(Ubiquitin-specific-processing protease 4) (Deubiquitinating enzyme4)(Ubiquitous nuclear protein homolog); (6248:) Ubiquitincarboxyl-terminal hydrolase 40 (Ubiquitin thioesterase 40)(Ubiquitin-specific-processing protease 40) (Deubiquitinating enzyme40); (6249:) Ubiquitin carboxyl-terminal hydrolase 42 (Ubiquitinthioesterase 42) (Ubiquitin-specific-processing protease 42)(Deubiquitinating enzyme 42); (6250:) Ubiquitin carboxyl-terminalhydrolase 43 (Ubiquitin thioesterase 43) (Ubiquitin-specific-processingprotease 43) (Deubiquitinating enzyme 43); (6251:) Ubiquitincarboxyl-terminal hydrolase 44 (Ubiquitin thioesterase 44)(Ubiquitin-specific-processing protease 44) (Deubiquitinating enzyme44); (6252:) Ubiquitin carboxyl-terminal hydrolase 46 (Ubiquitinthioesterase 46) (Ubiquitin-specific-processing protease 46)(Deubiquitinating enzyme 46); (6253:) Ubiquitin carboxyl-terminalhydrolase 47 (Ubiquitin thioesterase 47) (Ubiquitin-specific-processingprotease 47) (Deubiquitinating enzyme 47); (6254:) Ubiquitincarboxyl-terminal hydrolase 48 (Ubiquitin thioesterase 48)(Ubiquitin-specific-processing protease 48) (Deubiquitinating enzyme48); (6255:) Ubiquitin carboxyl-terminal hydrolase 49 (Ubiquitinthioesterase 49) (Ubiquitin-specific-processing protease 49)(Deubiquitinating enzyme 49); (6256:) Ubiquitin carboxyl-terminalhydrolase 5 (Ubiquitin thioesterase 5) (Ubiquitin-specific-processingprotease 5) (Deubiquitinating enzyme5) (Isopeptidase T); (6257:)Ubiquitin carboxyl-terminal hydrolase 51 (Ubiquitin thioesterase 51)(Ubiquitin-specific-processing protease 51) (Deubiquitinating enzyme51); (6258:) Ubiquitin carboxyl-terminal hydrolase 6 (Ubiquitinthioesterase 6) (Ubiquitin-specific-processing protease 6)(Deubiquitinating enzyme6) (Proto-oncogene TRE-2); (6259:) Ubiquitincarboxyl-terminal hydrolase 7 (Ubiquitin thioesterase 7)(Ubiquitin-specific-processing protease 7) (Deubiquitinating enzyme7)(Herpesvirus-associated ubiquitin-specific protease); (6260:) Ubiquitincarboxyl-terminal hydrolase 8 (Ubiquitin thioesterase 8)(Ubiquitin-specific-processing protease 8) (Deubiquitinating enzyme8)(hUBPy); (6261:) Ubiquitin carboxyl-terminal hydrolase BAP1(BRCA1-associated protein 1) (Cerebral protein 6); (6262:) ubiquitincarboxyl-terminal hydrolase CYLD isoform 1 [Homo sapiens]; (6263:)ubiquitin carboxyl-terminal hydrolase CYLD isoform 2 [Homo sapiens];(6264:) Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1)(Ubiquitin thioesterase L1) (Neuron cytoplasmic protein 9.5) (PGP9.5)(PGP9.5); (6265:) Ubiquitin carboxyl-terminal hydrolase isozyme L3(UCH-L3) (Ubiquitin thioesterase L3); (6266:) Ubiquitincarboxyl-terminal hydrolase isozyme L5 (UCH-L5) (Ubiquitin thioesteraseL5) (Ubiquitin C-terminal hydrolase UCH37); (6267:) ubiquitin carrierprotein [Homo sapiens]; (6268:) ubiquitin carrier protein E2—human;(6269:) ubiquitin carrier protein; (6270:) ubiquitin conjugatingenzyme—human (fragment); (6271:) ubiquitin conjugating enzyme [Homosapiens]; (6272:) ubiquitin conjugating enzyme 12 [Homo sapiens];(6273:) ubiquitin conjugating enzyme 6 [Homo sapiens]; (6274:) ubiquitinconjugating enzyme 7 interacting protein 5 isoform a variant [Homosapiens]; (6275:) ubiquitin conjugating enzyme 7 interacting protein 5isoform b variant [Homo sapiens]; (6276:) ubiquitin conjugating enzyme 9[Homo sapiens]; (6277:) ubiquitin conjugating enzyme 9; (6278:)ubiquitin conjugating enzyme E2 [Homo sapiens]; (6279:) ubiquitinconjugating enzyme E2, J2 isoform 1 [Homo sapiens]; (6280:) ubiquitinconjugating enzyme E2, J2 isoform 2 [Homo sapiens]; (6281:) ubiquitinconjugating enzyme E2, J2 isoform 3 [Homo sapiens]; (6282:) ubiquitinconjugating enzyme G2 [Homo sapiens]; (6283:) ubiquitin conjugatingenzyme homolog; (6284:) ubiquitin conjugating enzyme; (6285:) ubiquitinC-terminal hydrolase UCH37 [Homo sapiens]; (6286:) ubiquitin hydrolyzingenzyme 1 [Homo sapiens]; (6287:) ubiquitin hydrolyzing enzyme I [Homosapiens]; (6288:) Ubiquitin isopeptidase T [Homo sapiens]; (6289:)Ubiquitin Ligase; (6290:) ubiquitin ligase E3A isoform 1 [Homo sapiens];(6291:) Ubiquitin ligase LNX (Numb-binding protein 1) (Ligand ofNumb-protein X1); (6292:) Ubiquitin ligase protein DZIP3(DAZ-interacting protein 3) (RNA-binding ubiquitin ligase of 138 kDa)(hRUL138); (6293:) Ubiquitin ligase protein RING2 (RING finger protein2) (RING finger protein 1B) (RING1b) (RING finger protein BAP-1) (DinGprotein) (Huntingtin-interacting protein 2-interacting protein 3)(HIP2-interacting protein 3); (6294:) Ubiquitin ligase SIAH1 (Seven inabsentia homolog 1) (Siah-1) (Siah-1a); (6295:) Ubiquitin ligase SIAH2(Seven in absentia homolog 2) (Siah-2) (hSiah2); (6296:) ubiquitinprocessing protease [Homo sapiens]; (6297:) ubiquitin protein ligase E3Aisoform 1 [Homo sapiens]; (6298:) ubiquitin protein ligase E3A isoform 2[Homo sapiens]; (6299:) ubiquitin protein ligase E3A isoform 3 [Homosapiens]; (6300:) ubiquitin protein ligase E3B [Homo sapiens]; (6301:)ubiquitin protein ligase E3C [Homo sapiens]; (6302:) Ubiquitin proteinligase Praja1 (RING finger protein 70); (6303:) ubiquitin specificprotease 1 [Homo sapiens]; (6304:) ubiquitin specific protease 11 [Homosapiens]; (6305:) ubiquitin specific protease 14 isoform a [Homosapiens]; (6306:) ubiquitin specific protease 14 isoform b [Homosapiens]; (6307:) ubiquitin specific protease 15 [Homo sapiens]; (6308:)ubiquitin specific protease 16 isoform a [Homo sapiens]; (6309:)ubiquitin specific protease 16 isoform b [Homo sapiens]; (6310:)ubiquitin specific protease 2 isoform b [Homo sapiens]; (6311:)ubiquitin specific protease 20 [Homo sapiens]; (6312:) ubiquitinspecific protease 25 [Homo sapiens]; (6313:) ubiquitin specific protease28 [Homo sapiens]; (6314:) ubiquitin specific protease 29 [Homosapiens]; (6315:) ubiquitin specific protease 2b [Homo sapiens]; (6316:)ubiquitin specific protease 31 [Homo sapiens]; (6317:) ubiquitinspecific protease 33 isoform 1 [Homo sapiens]; (6318:) ubiquitinspecific protease 33 isoform 2 [Homo sapiens]; (6319:) ubiquitinspecific protease 33 isoform 3 [Homo sapiens]; (6320:) ubiquitinspecific protease 36 [Homo sapiens]; (6321:) ubiquitin specific protease42 [Homo sapiens]; (6322:) ubiquitin specific protease 48 [Homosapiens]; (6323:) ubiquitin specific protease 48 isoform a [Homosapiens]; (6324:) ubiquitin specific protease 51 [Homo sapiens]; (6325:)ubiquitin specific protease 7 (herpes virus-associated) [Homo sapiens];(6326:) ubiquitin specific protease 8 [Homo sapiens]; (6327:) ubiquitinspecific protease 9, X-linked isoform 3 [Homo sapiens]; (6328:)ubiquitin specific protease 9, X-linked isoform 4 [Homo sapiens];(6329:) ubiquitin specific protease 9, Y-linked [Homo sapiens]; (6330:)ubiquitin specific protease, proto-oncogene isoform a [Homo sapiens];(6331:) ubiquitin specific protease, proto-oncogene isoform b [Homosapiens]; (6332:) Ubiquitin thioesterase protein OTUB1 (Otubain-1) (OTUdomain-containing ubiquitin aldehyde-binding protein 1)(Ubiquitin-specific-processing protease OTUB1) (Deubiquitinating enzymeOTUB1); (6333:) Ubiquitin thioesterase protein OTUB2 (Otubain-2) (OTUdomain-containing ubiquitin aldehyde-binding protein 2)(Ubiquitin-specific-processing protease OTUB2) (Deubiquitinating enzymeOTUB2); (6334:) Ubiquitin; (6335:) Ubiquitin-activating enzyme E1 (A1S9protein); (6336:) Ubiquitin-activating enzyme E1 (A1S9T and BN75temperature sensitivity complementing) [Homo sapiens]; (6337:)ubiquitin-activating enzyme E1 [Homo sapiens]; (6338:)Ubiquitin-activating enzyme E1 domain-containing protein1(UFM1-activating enzyme) (Ubiquitin-activating enzyme 5) (ThiFP1);(6339:) Ubiquitin-activating enzyme E1 homolog (D8); (6340:)Ubiquitin-activating enzyme E1C (UBA3 homolog, yeast) [Homo sapiens];(6341:) ubiquitin-activating enzyme E1C isoform 1 [Homo sapiens];(6342:) ubiquitin-activating enzyme E1C isoform 2 [Homo sapiens];(6343:) ubiquitin-activating enzyme E1C isoform 3 [Homo sapiens];(6344:) Ubiquitin-activating enzyme E1-domain containing 1 [Homosapiens]; (6345:) ubiquitin-activating enzyme E1-domain containing 1isoform 1 [Homo sapiens]; (6346:) ubiquitin-activating enzyme E1-domaincontaining 1 isoform 2 [Homo sapiens]; (6347:) ubiquitin-activatingenzyme E1-like [Homo sapiens]; (6348:) Ubiquitin-activating enzymeE1-like 2 [Homo sapiens]; (6349:) ubiquitin-activating enzyme E1-relatedprotein; (6350:) ubiquitination factor E4A [Homo sapiens]; (6351:)ubiquitin-conjugating enzyme [Homo sapiens]; (6352:)ubiquitin-conjugating BIR-domain enzyme APOLLON [Homo sapiens]; (6353:)ubiquitin-conjugating enzyme [Homo sapiens]; (6354:)ubiquitin-conjugating enzyme 1 isoform [Homo sapiens]; (6355:)ubiquitin-conjugating enzyme 16 [Homo sapiens]; (6356:)Ubiquitin-conjugating enzyme 7-interacting protein 4(UbcM4-interactingprotein 4) (RING finger protein 144); (6357:) ubiquitin-conjugatingenzyme 9 (UBC9); (6358:) ubiquitin-conjugating enzyme E2 [Homo sapiens];(6359:) Ubiquitin-conjugating enzyme E2 A (Ubiquitin-protein ligase A)(Ubiquitin carrier protein A) (HR6A) (hHR6A); (6360:)Ubiquitin-conjugating enzyme E2 B (Ubiquitin-protein ligase B)(Ubiquitin carrier protein B) (HR6B) (hHR6B) (E2-17 kDa); (6361:)Ubiquitin-conjugating enzyme E2 C (Ubiquitin-protein ligase C)(Ubiquitin carrier protein C) (UbcH10); (6362:) Ubiquitin-conjugatingenzyme E2 D1 (Ubiquitin-protein ligase D1) (Ubiquitin carrier proteinD1) (UbCH5) (Ubiquitin-conjugating enzyme E2-17 kDa 1) (E2(17)KB 1);(6363:) Ubiquitin-conjugating enzyme E2 D2 (Ubiquitin-protein ligase D2)(Ubiquitin carrier protein D2) (Ubiquitin-conjugating enzyme E2-17 kDa2) (E2(17)KB 2); (6364:) ubiquitin-conjugating enzyme E2 D2 transcriptvariant 1 [Homo sapiens]; (6365:) Ubiquitin-conjugating enzyme E2 D3(Ubiquitin-protein ligase D3) (Ubiquitin carrier protein D3)(Ubiquitin-conjugating enzyme E2-17 kDa 3) (E2(17)KB 3); (6366:)Ubiquitin-conjugating enzyme E2 E1 (Ubiquitin-protein ligase E1)(Ubiquitin carrier protein E1) (UbCH6); (6367:) Ubiquitin-conjugatingenzyme E2 E2 (Ubiquitin-protein ligase E2) (Ubiquitin carrier proteinE2) (UbCH8); (6368:) Ubiquitin-conjugating enzyme E2 E3(Ubiquitin-protein ligase E3) (Ubiquitin carrier protein E3)(Ubiquitin-conjugating enzyme E2-23 kDa) (UbCH9) (UbcM2); (6369:)Ubiquitin-conjugating enzyme E2 G1 (Ubiquitin-protein ligase G1)(Ubiquitin carrier protein G1) (E217K) (UBC7); (6370:)Ubiquitin-conjugating enzyme E2 G2 (Ubiquitin-protein ligase G2)(Ubiquitin carrier protein G2); (6371:) Ubiquitin-conjugating enzyme E2H(Ubiquitin-protein ligase H) (Ubiquitin carrier protein H) (UbCH2)(E2-20K); (6372:) Ubiquitin-conjugating enzyme E2 J1 (Non-canonicalubiquitin-conjugating enzyme 1) (NCUBE1) (Yeast ubiquitin-conjugatingenzyme UBC6 homolog E) (HSUBC6e); (6373:) Ubiquitin-conjugating enzymeE2 J2 (Non-canonical ubiquitin-conjugating enzyme 2) (NCUBE2); (6374:)ubiquitin-conjugating enzyme E2 Kua-UEV isoform 1 [Homo sapiens];(6375:) ubiquitin-conjugating enzyme E2 Kua-UEV isoform 2 [Homosapiens]; (6376:) Ubiquitin-conjugating enzyme E2 L3 (Ubiquitin-proteinligase L3) (Ubiquitin carrier protein L3) (UbCH7) (E2-F1) (L-UBC);(6377:) Ubiquitin-conjugating enzyme E2 L6 (Ubiquitin-protein ligase L6)(Ubiquitin carrier protein L6) (UbCH8) (Retinoic acid-induced gene Bprotein) (RIG-B); (6378:) Ubiquitin-conjugating enzyme E2 N(Ubiquitin-protein ligase N) (Ubiquitin carrier protein N) (Ubc13)(Bendless-like ubiquitin-conjugating enzyme); (6379:)Ubiquitin-conjugating enzyme E2Q1 (Ubiquitin-protein ligase Q1)(Ubiquitin carrier protein Q1) (Protein NICE-5); (6380:)Ubiquitin-conjugating enzyme E2Q2 (Ubiquitin-protein ligase Q2)(Ubiquitin carrier protein Q2); (6381:) Ubiquitin-conjugating enzyme E2S (Ubiquitin-protein ligase S) (Ubiquitin carrier protein S)(Ubiquitin-conjugating enzyme E2-24 kDa) (E2-EPF5); (6382:)Ubiquitin-conjugating enzyme E2 T (Ubiquitin-protein ligase T)(Ubiquitin carrier protein T); (6383:) Ubiquitin-conjugating enzyme E2 U(Ubiquitin-protein ligase U) (Ubiquitin carrier protein U); (6384:)ubiquitin-conjugating enzyme E2 UbcH-ben [Homo sapiens]; (6385:)Ubiquitin-conjugating enzyme E2 variant 1 (UEV-1) (CROC-1)(Ubiquitin-conjugating enzyme variant Kua) (TRAF6-regulated IKKactivator 1 beta Uev1A); (6386:) Ubiquitin-conjugating enzyme E2 variant1 [Homo sapiens]; (6387:) ubiquitin-conjugating enzyme E2 variant 1isoform a [Homo sapiens]; (6388:) ubiquitin-conjugating enzyme E2variant 1 isoform c [Homo sapiens]; (6389:) ubiquitin-conjugating enzymeE2 variant 1 isoform d [Homo sapiens]; (6390:) Ubiquitin-conjugatingenzyme E2 variant 2 (MMS2) (Enterocyte differentiation-associated factorEDAF-1) (Enterocyte differentiation-promoting factor) (EDPF-1) (VitaminD3-inducible protein) (DDVit 1); (6391:) ubiquitin-conjugating enzyme E2variant 2 [Homo sapiens]; (6392:) Ubiquitin-conjugating enzyme E2, J1(UBC6 homolog, yeast) [Homo sapiens]; (6393:) ubiquitin-conjugatingenzyme E2, J1 [Homo sapiens]; (6394:) ubiquitin-conjugating enzyme E2,J1 variant [Homo sapiens]; (6395:) Ubiquitin-conjugating enzyme E2, J2(UBC6 homolog, yeast) [Homo sapiens]; (6396:) ubiquitin-conjugatingenzyme E2-17 kDa [Homo sapiens]; (6397:) Ubiquitin-conjugating enzymeE2-25 kDa (Ubiquitin-protein ligase) (Ubiquitin carrier protein)(E2(25K)) (Huntingtin-interacting protein 2) (HIP-2); (6398:)Ubiquitin-conjugating enzyme E2-32 kDa complementing (Ubiquitin-proteinligase) (Ubiquitin carrier protein) (E2-CDC34); (6399:)Ubiquitin-conjugating enzyme E2A (RAD6 homolog) [Homo sapiens]; (6400:)ubiquitin-conjugating enzyme E2A isoform 1 [Homo sapiens]; (6401:)ubiquitin-conjugating enzyme E2A isoform 1 variant [Homo sapiens];(6402:) ubiquitin-conjugating enzyme E2A isoform 2 [Homo sapiens];(6403:) ubiquitin-conjugating enzyme E2A isoform 3 [Homo sapiens];(6404:) Ubiquitin-conjugating enzyme E2B (RAD6 homolog) [Homo sapiens];(6405:) ubiquitin-conjugating enzyme E2B [Homo sapiens]; (6406:)Ubiquitin-conjugating enzyme E2C [Homo sapiens]; (6407:)ubiquitin-conjugating enzyme E2C isoform 1 [Homo sapiens]; (6408:)ubiquitin-conjugating enzyme E2C isoform 2 [Homo sapiens]; (6409:)ubiquitin-conjugating enzyme E2C isoform 3 [Homo sapiens]; (6410:)ubiquitin-conjugating enzyme E2C isoform 4 [Homo sapiens]; (6411:)ubiquitin-conjugating enzyme E2C isoform 5 [Homo sapiens]; (6412:)Ubiquitin-conjugating enzyme E2D1 (UBC4/5 homolog, yeast) [Homosapiens]; (6413:) ubiquitin-conjugating enzyme E2D1 [Homo sapiens];(6414:) Ubiquitin-conjugating enzyme E2D 2 (UBC4/5 homolog, yeast) [Homosapiens]; (6415:) ubiquitin-conjugating enzyme E2D 2 isoform 1 [Homosapiens]; (6416:) ubiquitin-conjugating enzyme E2D 2 isoform 2 [Homosapiens]; (6417:) Ubiquitin-conjugating enzyme E2D 3 (UBC4/5 homolog,yeast) [Homo sapiens]; (6418:) ubiquitin-conjugating enzyme E2D 3 [Homosapiens]; (6419:) ubiquitin-conjugating enzyme E2D 3 isoform 1 [Homosapiens]; (6420:) ubiquitin-conjugating enzyme E2D 3 isoform 2 [Homosapiens]; (6421:) ubiquitin-conjugating enzyme E2D 3 isoform 3 [Homosapiens]; (6422:) ubiquitin-conjugating enzyme E2D 4 (putative) [Homosapiens]; (6423:) Ubiquitin-conjugating enzyme E2E1 (UBC4/5 homolog,yeast) [Homo sapiens]; (6424:) ubiquitin-conjugating enzyme E2E1 isoform1 [Homo sapiens]; (6425:) ubiquitin-conjugating enzyme E2E 1 isoform 2[Homo sapiens]; (6426:) ubiquitin-conjugating enzyme E2E 2 (UBC4/5homolog, yeast) [Homo sapiens]; (6427:) Ubiquitin-conjugating enzyme E2E3 (UBC4/5 homolog, yeast) [Homo sapiens]; (6428:) ubiquitin-conjugatingenzyme E2E 3 [Homo sapiens]; (6429:) Ubiquitin-conjugating enzyme E2F(putative) [Homo sapiens]; (6430:) ubiquitin-conjugating enzyme E2G1(UBC7 homolog, C. elegans) [Homo sapiens]; (6431:) Ubiquitin-conjugatingenzyme E2G 1 (UBC7 homolog, yeast) [Homo sapiens]; (6432:)ubiquitin-conjugating enzyme E2G1 [Homo sapiens]; (6433:)Ubiquitin-conjugating enzyme E2G 2 (UBC7 homolog, yeast) [Homo sapiens];(6434:) ubiquitin-conjugating enzyme E2G 2 isoform 1 [Homo sapiens];(6435:) ubiquitin-conjugating enzyme E2G 2 isoform 2 [Homo sapiens];(6436:) ubiquitin-conjugating enzyme E2H (UBC8 homolog, yeast) [Homosapiens]; (6437:) ubiquitin-conjugating enzyme E2H isoform 1 [Homosapiens]; (6438:) ubiquitin-conjugating enzyme E2H isoform 2 [Homosapiens]; (6439:) Ubiquitin-conjugating enzyme E21 (UBC9 homolog, yeast)[Homo sapiens]; (6440:) ubiquitin-conjugating enzyme E21 [Homo sapiens];(6441:) ubiquitin-conjugating enzyme E21 variant [Homo sapiens]; (6442:)Ubiquitin-conjugating enzyme E2L 3 [Homo sapiens]; (6443:)ubiquitin-conjugating enzyme E2L 3 isoform 1 [Homo sapiens]; (6444:)ubiquitin-conjugating enzyme E2L 3 isoform 2 [Homo sapiens]; (6445:)Ubiquitin-conjugating enzyme E2L 6 [Homo sapiens]; (6446:)ubiquitin-conjugating enzyme E2L 6 isoform 1 [Homo sapiens]; (6447:)ubiquitin-conjugating enzyme E2L 6 isoform 2 [Homo sapiens]; (6448:)ubiquitin-conjugating enzyme E2-like isoform a [Homo sapiens]; (6449:)ubiquitin-conjugating enzyme E2-like isoform b [Homo sapiens]; (6450:)Ubiquitin-conjugating enzyme E2M (UBC12 homolog, yeast) [Homo sapiens];(6451:) ubiquitin-conjugating enzyme E2M [Homo sapiens]; (6452:)Ubiquitin-conjugating enzyme E2N (UBC13 homolog, yeast) [Homo sapiens];(6453:) ubiquitin-conjugating enzyme E2N [Homo sapiens]; (6454:)ubiquitin-conjugating enzyme E2N-like [Homo sapiens]; (6455:)ubiquitin-conjugating enzyme E20 [Homo sapiens]; (6456:)ubiquitin-conjugating enzyme E2Q (putative) [Homo sapiens]; (6457:)ubiquitin-conjugating enzyme E2Q (putative) 2 [Homo sapiens]; (6458:)ubiquitin-conjugating enzyme E2Q [Homo sapiens]; (6459:)Ubiquitin-conjugating enzyme E2R 2 [Homo sapiens]; (6460:)ubiquitin-conjugating enzyme E2S [Homo sapiens]; (6461:)ubiquitin-conjugating enzyme E2T (putative) [Homo sapiens]; (6462:)ubiquitin-conjugating enzyme E2U (putative) [Homo sapiens]; (6463:)Ubiquitin-conjugating enzyme E2W (putative) [Homo sapiens]; (6464:)ubiquitin-conjugating enzyme E2W (putative) isoform 1 [Homo sapiens];(6465:) ubiquitin-conjugating enzyme E2W (putative) isoform 2 [Homosapiens]; (6466:) ubiquitin-conjugating enzyme E2W (putative) isoform 3[Homo sapiens]; (6467:) ubiquitin-conjugating enzyme E2Z (putative)[Homo sapiens]; (6468:) ubiquitin-conjugating enzyme HBUCE1 [Homosapiens]; (6469:) ubiquitin-conjugating enzyme isolog [Homo sapiens];(6470:) ubiquitin-conjugating enzyme RIG-B [Homo sapiens]; (6471:)ubiquitin-conjugating enzyme UBC3B [Homo sapiens]; (6472:)ubiquitin-conjugating enzyme UbCH2 [Homo sapiens]; (6473:)ubiquitin-conjugating enzyme UbCH6 [Homo sapiens]; (6474:)ubiquitin-conjugating enzyme UbCH7 [Homo sapiens]; (6475:)ubiquitin-conjugating enzyme UbcM2 [Homo sapiens]; (6476:)ubiquitin-conjugating enzyme variant Kua [Homo sapiens]; (6477:)ubiquitin-conjugating enzyme, UBC9 [Homo sapiens]; (6478:)ubiquitin-conjugating enzyme; (6479:) ubiquitin-conjugating enzyme E2[Homo sapiens]; (6480:) Ubiquitin-fold modifier conjugating enzyme 1[Homo sapiens]; (6481:) Ubiquitin-like 1-activating enzyme E1A(SUMO-1-activating enzyme subunit 1); (6482:) Ubiquitin-like1-activating enzyme E1B (SUMO-1-activating enzyme subunit 2)(Anthracycline-associated resistance ARX); (6483:) Ubiquitin-like PHDand RING finger domain-containing protein 2(Ubiquitin-like-containingPHD and RING finger domains protein 2) (Np95/ICBP90-like RING fingerprotein) (Np95-like RING finger protein) (Nuclear zinc finger proteinNp97) (RING finger protein107); (6484:) “ubiquitin-like proteinactivating enzyme; sentrin activating enzyme [Homo sapiens].”; (6485:)Ubiquitin-protein E3 ligase Topors (SUMO1-protein E3 ligase Topors)(Topoisomerase I-binding RING finger protein) (Topoisomerase I-bindingarginine/serine-rich protein) (Tumor suppressor p53-binding protein 3)(p53-binding protein 3) (p53BP3); (6486:) Ubiquitin-protein ligase BRE1A(BRE1-A) (hBRE1) (RING finger protein 20); (6487:) Ubiquitin-proteinligase BRE1B (BRE1-B) (RING finger protein 40) (95 kDaretinoblastoma-associated protein) (RBP95); (6488:) ubiquitin-proteinligase E1 homolog—human; (6489:) Ubiquitin-protein ligase E3A (E6APubiquitin-protein ligase) (Oncogenic protein-associated protein E6-AP)(Human papillomavirus E6-associated protein) (NY-REN-54 antigen);(6490:) Ubiquitin-protein ligase E3C; (6491:) Ubiquitin-protein ligaseEDD1 (Hyperplastic discs protein homolog) (hHYD) (Progestin-inducedprotein); (6492:) ubiquitin-specific processing protease [Homo sapiens];(6493:) ubiquitin-specific protease 12-like 1 [Homo sapiens]; (6494:)ubiquitin-specific protease 21 [Homo sapiens]; (6495:)ubiquitin-specific protease 26 [Homo sapiens]; (6496:)ubiquitin-specific protease 3 [Homo sapiens]; (6497:) ubiquitin-specificprotease 31 [Homo sapiens]; (6498:) ubiquitin-specific protease 7isoform [Homo sapiens]; (6499:) U-box domain containing 5 isoform a[Homo sapiens]; (6500:) U-box domain containing 5 isoform b [Homosapiens]; (6501:) UDP glucuronosyltransferase (EC 2.4.1.-) 1A10precursor—human; (6502:) UDP glycosyltransferase 1 family, polypeptideA1 precursor [Homo sapiens]; (6503:) UDP glycosyltransferase 1 family,polypeptide A10 precursor [Homo sapiens]; (6504:) UDPglycosyltransferase 1 family, polypeptide A3 precursor [Homo sapiens];(6505:) UDP glycosyltransferase 1 family, polypeptide A4 precursor [Homosapiens]; (6506:) UDP glycosyltransferase 1 family, polypeptide A5precursor [Homo sapiens]; (6507:) UDP glycosyltransferase 1 family,polypeptide A6 isoform 1 precursor [Homo sapiens]; (6508:) UDPglycosyltransferase 1 family, polypeptide A6 isoform 2 [Homo sapiens];(6509:) UDP glycosyltransferase 1 family, polypeptide A7 precursor [Homosapiens]; (6510:) UDP glycosyltransferase 1 family, polypeptide A8precursor [Homo sapiens]; (6511:) UDP glycosyltransferase 1 family,polypeptide A9 precursor [Homo sapiens]; (6512:) UDP glycosyltransferase2 family, polypeptide B15 [Homo sapiens]; (6513:) UDPglycosyltransferase 2 family, polypeptide B4 [Homo sapiens]; (6514:) UDPglycosyltransferase 8 (UDP-galactose ceramidegalactosyltransferase)[Homo sapiens]; (6515:) UDP-Gal:betaGlcNAc beta1,3-galactosyltransferase 5 [Homo sapiens]; (6516:) UDP-Gal:betaGlcNAcbeta 1,4-galactosyltransferase 1, membrane-bound form [Homo sapiens];(6517:) UDP-Gal:betaGlcNAc beta 1,4-galactosyltransferase 2 [Homosapiens]; (6518:) UDP-Gal:betaGlcNAc beta 1,4-galactosyltransferase 3[Homo sapiens]; (6519:) UDP-Gal:betaGlcNAc beta1,4-galactosyltransferase 4 [Homo sapiens]; (6520:) UDP-Gal:betaGlcNAcbeta 1,4-galactosyltransferase 5 [Homo sapiens]; (6521:)UDP-Gal:betaGlcNAc beta 1,4-galactosyltransferase 6 [Homo sapiens];(6522:) UDP-galactose-4-epimerase [Homo sapiens]; (6523:)UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 1 [Homosapiens]; (6524:) UDP-GlcNAc:betaGalbeta-1,3-N-acetylglucosaminyltransferase 2 [Homo sapiens]; (6525:)UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 3 [Homosapiens]; (6526:) UDP-GlcNAc:betaGalbeta-1,3-N-acetylglucosaminyltransferase 4 [Homo sapiens]; (6527:)UDP-GlcNAc:betaGal beta-1,3-N-1-acetylglucosaminyltransferase 5 [Homosapiens]; (6528:) UDP-GlcNAc:betaGalbeta-1,3-N-acetylglucosaminyltransferase 6 [Homo sapiens]; (6529:)UDP-glucose 4-epimerase (Galactowaldenase) (UDP-galactose-4-epimerase);(6530:) UDP-glucose pyrophosphorylase 2 isoform a [Homo sapiens];(6531:) UDP-glucose pyrophosphorylase 2 isoform b [Homo sapiens];(6532:) UDP-glucuronate decarboxylase 1 [Homo sapiens]; (6533:)UDP-glucuronosyltransferase 1-1 precursor (UDP-glucuronosyltransferase1A1) (UDPGT) (UGT1*1) (UGT1-01) (UGT1.1) (UGT-1A) (UGT1A)(Bilirubin-specific UDPGT isozyme 1) (HUG-BR1); (6534:)UDP-glucuronosyltransferase 1-6 precursor (UDP-glucuronosyltransferase1A6) (UDPGT) (UGT1*6) (UGT1-06) (UGT1.6) (UGT-1F) (UGT1F)(Phenol-metabolizing UDP-glucuronosyltransferase); (6535:)UDP-glucuronosyltransferase 2B15 precursor (UDPGT) (UDPGTh-3) (HLUG4);(6536:) UDP-glucuronosyltransferase 2B17 precursor (UDPGT)(C19-steroid-specific UDP-glucuronosyltransferase); (6537:)UDP-glucuronosyltransferase 2B4 precursor (UDPGT) (Hyodeoxycholic acid)(HLUG25) (UDPGTh-1); (6538:) UDP-glucuronyltransferase-S [Homo sapiens];(6539:) UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase[Homo sapiens]; (6540:) UDP-N-acetylglucosamine-2-epimerase [Homosapiens]; (6541:)UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase [Homosapiens]; (6542:) UDP-N-acetylglucosamine—dolichyl-phosphateN-acetylglucosamine phosphotransferase (GPT) (G1 PT)(N-acetylglucosamine-1-phosphate transferase) (GlcNAc-1-P transferase);(6543:)UDP-N-acetylglucosamine-dolichyl-phosphateN-acetylglucosaminephosphotransferaseisoform a [Homo sapiens]; (6544:)UDP-N-acetylglucosamine-dolichyl-phosphateN-acetylglucosaminephosphotransferaseisoform b [Homo sapiens]; (6545:) “UDP-N-acetylhexosaminepyrophosphorylase (Antigen X) (AGX) (Sperm-associated antigen 2)[Includes:) UDP-N-acetylgalactosamine pyrophosphorylase (AGX-1);UDP-N-acetylglucosamine pyrophosphorylase (AGX-2)].”; (6546:)UDP-N-acteylglucosamine pyrophosphorylase 1 [Homo sapiens]; (6547:)UEV-1 [Homo sapiens]; (6548:) UEV1As [Homo sapiens]; (6549:) UEV1 Bs[Homo sapiens]; (6550:) Ufm1-conjugating enzyme 1 (Ubiquitin-foldmodifier-conjugating enzyme 1); (6551:) Ufm1-conjugating enzyme 1 [Homosapiens]; (6552:) UGA suppressor tRNA-associated protein(tRNA(Ser/Sec)-associated antigenic protein) (SLA/LP autoantigen)(Soluble liver antigen) (SLA) (Liver-pancreas antigen) (LP) (SLA-p35);(6553:) UMP synthase [Homo sapiens]; (6554:) UMP-CMP kinase (Cytidylatekinase) (Deoxycytidylate kinase) (Cytidine monophosphate kinase)(Uridine monophosphate/cytidine monophosphate kinase) (UMP/CMP kinase)(UMP/CMPK) (Uridinemonophosphate kinase); (6555:) UMP-CMP kinase [Homosapiens]; (6556:) UnpEL [Homo sapiens]; (6557:) UnpES [Homo sapiens];(6558:) u-plasminogen activator receptor form 1 precursor—human; (6559:)upstream binding protein 1 (LBP-1a) [Homo sapiens]; (6560:)Upstream-binding protein 1 (LBP-1); (6561:) Uracil-DNA glycosylase(UDG); (6562:) uracil-DNA glycosylase isoform UNG1 precursor [Homosapiens]; (6563:) uracil-DNA glycosylase isoform UNG2 [Homo sapiens];(6564:) Urate Transporter 1 (URAT1); (6565:) Urease; (6566:) Uridinediphosphate glucose pyrophosphatase (UDPG pyrophosphatase) (UGPPase)(Nucleoside diphosphate-linked moiety X motif 14) (Nudix motif 14);(6567:) uridine diphosphate glucose pyrophosphatase [Homo sapiens];(6568:) uridine phosphorylase (EC 2.4.2.3)-2—human; (6569:) UridinePhosphorylase (UrdPase); (6570:) uridine-cytidine kinase 2 [Homosapiens]; (6571:) UROD [Homo sapiens]; (6572:) urokinase plasminogenactivator preproprotein [Homo sapiens]; (6573:) Urokinase plasminogenactivator surface receptor precursor (uPAR) (U-PAR) (Monocyte activationantigen Mo3) (CD87 antigen); (6574:) Urokinase-type plasminogenactivator (uPA); (6575:) Urokinase-type plasminogen activator receptor(uPAR); (6576:) Uronyl 2-sulfotransferase; (6577:) uroporphyrinogendecarboxylase (EC 4.1.1.37); (6578:) Uroporphyrinogen decarboxylase(URO-D) (UPD); (6579:) uroporphyrinogen decarboxylase [Homo sapiens];(6580:) uroporphyrinogen decarboxylase; (6581:) Urotensin II (UT-II)Receptor; (6582:) Urotensin II receptor (UR-II-R) (G-protein coupledreceptor 14); (6583:) USP48 protein [Homo sapiens]; (6584:) usurpin beta[Homo sapiens]; (6585:) Usurpin-alpha [Homo sapiens]; (6586:)Usurpin-beta [Homo sapiens]; (6587:) Usurpin-gamma [Homo sapiens];(6588:) UTP-hexose-1-phosphate uridylyltransferase (EC 2.7.7.10)—human;(6589:) UURF2 ubiquitin ligase [Homo sapiens]; (6590:) Vacuolar ATPsynthase 16 kDa proteolipid subunit; (6591:) Vacuolar ATP synthasecatalytic subunit A, osteoclast isoform (V-ATPase subunit A 2) (Vacuolarproton pump alpha subunit 2) (V-ATPase 69 kDa subunit 2) (Isoform H068);(6592:) Vacuolar ATP synthase catalytic subunit A, ubiquitous isoform(V-ATPase subunit A 1) (Vacuolar proton pump alpha subunit 1) (V-ATPase69 kDa subunit 1) (Isoform VA68); (6593:) Vacuolar ATP synthase subunitB, brain isoform (V-ATPase B2subunit) (Vacuolar proton pump β isoform 2)(Endomembrane proton pump 58 kDa subunit) (H057); (6594:) Vacuolar ATPsynthase subunit B, kidney isoform (V-ATPase B1 subunit) (Vacuolarproton pump β isoform 1) (Endomembrane proton pump 58 kDa subunit);(6595:) Vacuolar ATP synthase subunit C (V-ATPase C subunit) (Vacuolarproton pump C subunit); (6596:) Vacuolar ATP synthase subunit D(V-ATPase D subunit) (Vacuolar proton pump D subunit) (V-ATPase 28 kDaaccessory protein); (6597:) Vacuolar ATP synthase subunit d (V-ATPase dsubunit) (Vacuolar proton pump subunit d) (V-ATPase AC39 subunit)(V-ATPase 40 kDa accessory protein) (P39) (32 kDa accessory protein);(6598:) Vacuolar ATP synthase subunit E (V-ATPase E subunit) (Vacuolarproton pump E subunit) (V-ATPase 31 kDa subunit) (P31); (6599:) VacuolarATP synthase subunit F (V-ATPase F subunit) (Vacuolar proton pump Fsubunit) (V-ATPase 14 kDa subunit); (6600:) Vacuolar ATP synthasesubunit G1 (V-ATPase G subunit 1) (Vacuolar proton pump G subunit 1)(V-ATPase 13 kDa subunit 1) (Vacuolar ATPsynthase subunit M16); (6601:)Vacuolar ATP synthase subunit G 2 (V-ATPase G subunit 2) (Vacuolarproton pump G subunit 2) (V-ATPase 13 kDa subunit 2); (6602:) VacuolarATP synthase subunit G 3 (V-ATPase G subunit 3) (Vacuolar proton pump Gsubunit 3) (V-ATPase 13 kDa subunit 3); (6603:) Vacuolar ATP synthasesubunit H (V-ATPase H subunit) (Vacuolar proton pump subunit H)(V-ATPase 50/57 kDa subunits) (Vacuolar proton pump subunit SFD) (VMA13)(Nef-binding protein 1) (NBP1); (6604:) vacuolar ATPase subunit H [Homosapiens]; (6605:) vacuolar H+ ATPase C2 isoform a [Homo sapiens];(6606:) vacuolar H+ ATPase C2 isoform b [Homo sapiens]; (6607:) vacuolarH+ ATPase E1 isoform a [Homo sapiens]; (6608:) vacuolar H+ ATPase E1isoform b [Homo sapiens]; (6609:) vacuolar H+ ATPase E1 isoform c [Homosapiens]; (6610:) vacuolar H+ ATPase G1 [Homo sapiens]; (6611:) vacuolarH+ ATPase B2 [Homo sapiens]; (6612:) Vacuolar Hydrogen TransportingATPase (V-ATPase); (6613:) Vacuolar protein sorting-associated protein26A (Vesicle protein sorting 26A) (hVPS26); (6614:) Vacuolar proteinsorting-associated protein 26B (Vesicle protein sorting 26B); (6615:)Vacuolar protein sorting-associated protein 29 (Vesicle protein sorting29) (hVPS29) (PEP11); (6616:) Vacuolar protein sorting-associatedprotein 35 (Vesicle protein sorting 35) (hVPS35) (Maternal-embryonic 3);(6617:) vacuolar proton pump subunit SFD alpha isoform [Homo sapiens];(6618:) Vacuolar proton translocating ATPase 116 kDa subunit a isoform 1(V-ATPase 116 kDa isoform a1) (Clathrin-coated vesicle/synaptic vesicleproton pump 116 kDa subunit) (Vacuolar proton pump subunit 1) (Vacuolaradenosine triphosphatase subunit Ac 16); (6619:) Vacuolar protontranslocating ATPase 116 kDa subunit a isoform 2(V-ATPase 116 kDaisoform a2) (TJ6); (6620:) Vacuolar proton translocating ATPase 116 kDasubunit a isoform 3(V-ATPase 116 kDa isoform a3) (Osteoclastic protonpump 116 kDa subunit) (OC-116 kDa) (OC116) (T-cell immune regulator 1)(T cell immune response cDNA7 protein) (TIRC7); (6621:) Vacuolar protontranslocating ATPase 116 kDa subunit a isoform 4(V-ATPase 116 kDaisoform a4) (Vacuolar proton translocating ATPase 116 kDa subunit akidney isoform); (6622:) v-akt murine thymoma viral oncogene homolog 1[Homo sapiens]; (6623:) v-akt murine thymoma viral oncogene homolog 2[Homo sapiens]; (6624:) Valacyclovir hydrolase precursor (VACVase)(Biphenyl hydrolase-like protein) (Biphenyl hydrolase-related protein)(Bph-rp) (Breast epithelial mucin-associated antigen) (MCNAA); (6625:)valosin containing protein (p97)/p47 complex interacting protein 1 [Homosapiens]; (6626:) Valyl-tRNA synthetase (Valine—tRNA ligase) (VaIRS)(Protein G7a); (6627:) Vanilloid Receptor 1 (VR1); (6628:) VascularAdhesion Protein-1 (VAP-1) Receptor; (6629:) vascular adhesion protein-1[Homo sapiens]; (6630:) Vascular AdhesionProtein-1/Semicarbazide-Sensitive Amine Oxidase (VAP-1/SSAO); (6631:)“vascular adhesion protein-1; semicarbazide sensitive amine oxidase;copper-containing amine oxidase homolog [Homo sapiens].”; (6632:)Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression; (6633:) VascularEndothelial Growth Factor (VEGF); (6634:) Vascular Endothelial GrowthFactor (VEGF) Receptor; (6635:) Vascular Endothelial Growth Factor 121(VEGF121); (6636:) Vascular Endothelial Growth Factor 145 (VEGF145);(6637:) Vascular Endothelial Growth Factor 165 (VEGF165); (6638:)Vascular Endothelial Growth Factor 165 (VEGF165) Receptor; (6639:)vascular endothelial growth factor A isoform a precursor [Homo sapiens];(6640:) vascular endothelial growth factor A isoform b precursor [Homosapiens]; (6641:) vascular endothelial growth factor A isoform cprecursor [Homo sapiens]; (6642:) vascular endothelial growth factor Aisoform d precursor [Homo sapiens]; (6643:) vascular endothelial growthfactor A isoform e precursor [Homo sapiens]; (6644:) vascularendothelial growth factor A isoform f precursor [Homo sapiens]; (6645:)vascular endothelial growth factor A isoform g precursor [Homo sapiens];(6646:) Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1); (6647:)Vascular endothelial growth factor receptor 1 precursor (VEGFR-1)(Vascular permeability factor receptor) (Tyrosine-protein kinasereceptor FLT) (Flt-1) (Tyrosine-protein kinase FRT) (Fms-like tyrosinekinase 1); (6648:) Vascular Endothelial Growth Factor Receptor 2(VEGFR-2); (6649:) Vascular endothelial growth factor receptor 2precursor (VEGFR-2) (Kinase insert domain receptor) (Protein-tyrosinekinase receptor Flk-1) (CD309 antigen); (6650:) Vascular endothelialgrowth factor receptor 3 precursor (VEGFR-3) (Tyrosine-protein kinasereceptor FLT4); (6651:) Vascular Endothelial Growth Factor Receptor1-Tyrosine Kinase (VEGFR1-TK); (6652:) Vascular Endothelial GrowthFactor Receptor2-Tyrosine Kinase (VEGFR2-TK); (6653:) VascularEndothelial Growth Factor Receptor-Tyrosine Kinase (VEGFR-TK); (6654:)Vascular Endothelial-Cadherin (VE-Cadherin); (6655:) VasoactiveIntestinal Peptide Receptor 1 (VPAC1); (6656:) vasoactive intestinalpeptide receptor-related protein precursor (clone hIVR5)—human; (6657:)Vasoactive intestinal polypeptide receptor 1 precursor (VIP-R-1)(Pituitary adenylate cyclase-activating polypeptide type II receptor)(PACAP type II receptor) (PACAP-R-2); (6658:) Vasoactive intestinalpolypeptide receptor 2 precursor (VIP-R-2) (Pituitary adenylatecyclase-activating polypeptide type III receptor) (PACAP type IIIreceptor) (PACAP-R-3) (Helodermin-preferring VIP receptor); (6659:)Vasopressin V1a receptor (V1aR) (Vascular/hepatic-type argininevasopressin receptor) (Antidiuretic hormone receptor 1a) (AVPRV1a);(6660:) Vasopressin V1 b receptor (V1bR) (AVPR V1b) (VasopressinV3receptor) (AVPR V3) (Antidiuretic hormone receptor 1b); (6661:)Vasopressin V2 receptor (Renal-type arginine vasopressin receptor)(Antidiuretic hormone receptor) (AVPR V2); (6662:) VELF1904 [Homosapiens]; (6663:) Very low-density lipoprotein receptor precursor (VLDLreceptor) (VLDL-R); (6664:) Very-long-chain acyl-CoA synthetase (VLCS)(Very-long-chain-fatty-acid-CoA ligase) (VLACS) (THCA-CoA ligase)(Fatty-acid-coenzyme A ligase, very long-chain 1)(Long-chain-fatty-acid—CoA ligase) (Fatty acid transport protein2)(FATP-2) (Solute carrier family 27 member 2); (6665:) vesicle dockingprotein p115 [Homo sapiens]; (6666:) Vesicle-associated membrane protein8 (VAMP-8) (Endobrevin) (EDB); (6667:) v-ets erythroblastosis virus E26oncogene homolog 1 [Homo sapiens]; (6668:) visfatin precursor [Homosapiens]; (6669:) Visual pigment-like receptor peropsin; (6670:) vitaminD (1,25-dihydroxy vitamin D3) receptor [Homo sapiens]; (6671:) vitamin Dinducible protein [Homo sapiens]; (6672:) Vitamin D Receptor (VDR);(6673:) Vitamin D3 receptor (VDR) (1,25-dihydroxy vitamin D3 receptor);(6674:) Vitamin K; (6675:) Vitamin K epoxide reductase complex subunit 1(Vitamin K12,3-epoxide reductase subunit 1); (6676:) vitamin K epoxidereductase complex, subunit 1 isoform 1 [Homo sapiens]; (6677:) vitamin Kepoxide reductase complex, subunit 1 isoform 2 [Homo sapiens]; (6678:)“Vitamin K-dependent protein C precursor (Autoprothrombin IIA)(Anticoagulant protein C) (Blood coagulation factor XIV)[Contains:Vitamin K-dependent protein C light chain; Vitamin K-dependentprotein C heavy chain; Activation peptide].”; (6679:) VitaminK-dependent protein Z precursor; (6680:) v-kit Hardy-Zuckerman 4 felinesarcoma viral oncogene homolog precursor [Homo sapiens]; (6681:) v-mafmusculoaponeurotic fibrosarcoma oncogene homolog G [Homo sapiens];(6682:) v-maf musculoaponeurotic fibrosarcoma oncogene homolog isoform a[Homo sapiens]; (6683:) v-maf musculoaponeurotic fibrosarcoma oncogenehomolog isoform b[Homo sapiens]; (6684:) Vomeronasal type-1 receptor 1(V1 r-like receptor 1) (Vomeronasalol factory receptor chromosome 19subtype I member 1) (V3r-related gene) (hGPCR24); (6685:) Vomeronasaltype-1 receptor 2 (V1r-like receptor 2) (hGPCR25); (6686:) Vomeronasaltype-1 receptor 3 (V1r-like receptor 3); (6687:) Vomeronasal type-1receptor 4 (V1r-like receptor 4) (hGPCR27); (6688:) Vomeronasal type-1receptor 5 (V1r-like receptor 5) (hGPCR26); (6689:) Von Hippel-Lindaudisease tumor suppressor (PVHL) (G7 protein); (6690:) von Hippel-Lindautumor suppressor isoform 1 [Homo sapiens]; (6691:) von Hippel-Lindautumor suppressor isoform 2 [Homo sapiens]; (6692:) von Willebrand Factor(vWF) Receptor; (6693:) von Willebrand factor preproprotein [Homosapiens]; (6694:) v-raf murine sarcoma 3611 viral oncogene homolog [Homosapiens]; (6695:) v-raf murine sarcoma viral oncogene homolog B1 [Homosapiens]; (6696:) v-raf-1 murine leukemia viral oncogene homolog 1 [Homosapiens]; (6697:) v-rel reticuloendotheliosis viral oncogene homolog A,nuclear factor of kappa light polypeptide gene enhancer in B-cells 3,p65 [Homo sapiens]; (6698:) wax synthase [Homo sapiens]; (6699:)Weel-like protein kinase (Weel A kinase) (WEE1hu); (6700:) Wernersyndrome protein [Homo sapiens]; (6701:) Wiskott-Aldrich syndromeprotein [Homo sapiens]; (6702:) Wnt; (6703:) WW, C2 and coiled-coildomain containing 1 [Homo sapiens]; (6704:) xanthine dehydrogenase [Homosapiens]; (6705:) “Xanthine dehydrogenase/oxidase [Includes:) Xanthinedehydrogenase (XD); Xanthine oxidase (XO) (Xanthine oxidoreductase)].”;(6706:) Xanthine Oxidase (XO); (6707:) X-Linked inhibitor of ApoptosisProtein (XIAP); (6708:) X-linked interleukin-1 receptor accessoryprotein-like 1 precursor (IL1 RAPL-1) (Oligophrenin-4) (Threeimmunoglobulin domain-containing IL-1 receptor-related 2) (TIGIRR-2);(6709:) X-linked interleukin-1 receptor accessory protein-like 2precursor (ILL RAPL-2-related protein) (Interleukin-1 receptor 9) (IL-1R9) (IL-1 receptor accessory protein-like 2) (Three immunoglobulindomain-containing IL-1 receptor-related 1) (TIGIRR-1); (6710:) X-linkedphosphate regulating endopeptidase homolog [Homo sapiens]; (6711:)X-prolyl aminopeptidase (aminopeptidase P)₁, soluble [Homo sapiens];(6712:) X-prolyl aminopeptidase 2, membrane-bound [Homo sapiens];(6713:) xylosyl protein beta 1,4-galactosyltransferase 7 [Homo sapiens];(6714:) Xylosyltransferase 1 (Xylosyltransferase I) (XyIT-I) (XT-I)(Peptide O-xylosyltransferase 1); (6715:) Xylosyltransferase 2(Xylosyltransferase II) (xyIT-II) (XT-II) (Peptide O-xylosyltransferase1); (6716:) xylosyltransferase I [Homo sapiens]; (6717:)xylosyltransferase II [Homo sapiens]; (6718:) Xaa-Pro aminopeptidase 1(X-Pro aminopeptidase 1) (X-prolylaminopeptidase 1, soluble) (Cytosolicaminopeptidase P) (Soluble aminopeptidase P) (sAmp) (Aminoacylprolineaminopeptidase); (6719:) Xaa-Pro dipeptidase (X-Pro dipeptidase)(Proline dipeptidase) (Prolidase) (Imidodipeptidase); (6720:) Xaa-Prodipeptidase [Homo sapiens]; (6721:) Yama protein; (6722:) Ymer proteinlong isoform [Homo sapiens]; (6723:) Ymer protein short isoform [Homosapiens]; (6724:) YOD1 OTU deubiquinating enzyme 1 homolog [Homosapiens]; (6725:) Zinc finger FYVE domain-containing protein 9 (Mothersagainst decapentaplegic homolog-interacting protein) (Madh-interactingprotein) (Smad anchor for receptor activation) (Receptor activationanchor) (hSARA) (Novel serine protease) (NSP); (6726:) zinc fingerprotein 146 [Homo sapiens]; (6727:) zinc finger protein Cezanne [Homosapiens]; (6728:) Zinc finger protein OZF (Only zinc finger protein)(Zinc finger protein 146); (6729:) zinc metalloproteinase STE24 homolog[Homo sapiens]; (6730:) Zinc phosphodiesterase ELAC protein 1(Ribonuclease Z1) (RNase Z1) (tRNase Z1) (tRNA 3 endonuclease 1) (ElaChomolog protein 1) (Deleted in Ma29); (6731:) Zinc phosphodiesteraseELAC protein 2 (Ribonuclease Z 2) (RNase Z2) (tRNase Z 2) (tRNA 3endonuclease 2) (ElaC homolog protein 2) (Heredity prostate cancerprotein 2); (6732:) Zona pellucida sperm-binding protein 2 precursor(Zona pellucida glycoprotein ZP2) (Zona pellucida protein A)

Methods for Isolating “Lead Compounds”

The present invention in one embodiment is also directed to a method forisolating novel “drug leads” or “lead compounds” from libraries ofdifferent molecules synthesised by the methods of the invention. A “druglead” or “lead compound” is a compound which may not in itself besuitable as a drug, but which exhibits a number of characteristics whichare interesting when viewed from the point of view of medical therapy.

The reasons why such “lead compounds” are often unsuitable could betoxicity, unsuitable pharmacokinetic or pharmacodynamic properties,difficulties relating to preparation and purification etc. In suchcases, the “lead compound” is used as a model for de novo synthesis ofother chemical compounds which are designed so as to be related to theactive part of the lead compound in 3D structure and distribution ofcharged, polar and non-polar groups.

This approach can be refined by initially identifying the members of thelibrary by methods of structure-based or nonstructure based computerdrug-modelling. Suitable non-structure based methods are disclosed ine.g. U.S. Pat. No. 5,307,287 and U.S. Pat. No. 5,025,388 (a method knownas COMFA). An alternative is HASL (Hypothetical Active Site Lattice;Hypothesis Software). Both these methods are based on 3D-QSAR. Afeasible structure-based approach is e.g. disclosed in WO 95/06293.

In view of the above, the present invention also pertains to a methodfor the preparation of a medicinal product, the method comprising thesteps of

-   a) selecting a chemical compound by the methods of the invention    described above,-   b) performing pre-clinical tests with the chemical compound in order    to assess the suitability thereof as a medicinal product,-   c) entering, if the chemical compound is deemed suitable in step    (b), clinical trials using the chemical compound in order to obtain    market authorization for a medicinal product including the chemical    compound as a pharmaceutically active substance, and-   d) upon grant of a market authorization, admixing the chemical    compound with a pharmaceutically acceptable carrier excipient or    diluent and marketing the thus obtained medicinal product.

The above-outlined methods should take into consideration all necessaryrequirements in order to meet GCP and GMP standards.

Additional preferred uses and embodiments of the present invention isdisclosed herein below. A number of assays which can be used to verifyor identify an effect or property of a molecule identified by one ormore methods of the present invention can be performed by a personskilled in the art.

In embodiments of the present invention, the bioactive species encodingit is used to identify pharmaceutically relevant target molecules, i.e.the molecules with which the bioactive species can form an interaction.As will be appreciated by those in the art, there can be primary targetmolecules to which the bioactive species binds or acts upon directly andthere can be secondary target molecules, which are part of a signallingpathway affected by the bioactive species; the latter might be termed“validated targets”.

In one embodiment, the present methods are useful in cancerapplications. The ability to rapidly and specifically kill tumor cellsis a cornerstone of cancer chemotherapy. In general, using the methodsof the present invention, bioactive species can be identified which,when introduced into any tumor cell (primary or cultured), induceapoptosis, cell death loss of cell division or decreased cell growth.This can be done de novo, or by biased randomization toward known canceragents, such as angiostatin, which inhibits blood vessel wall growth.According to one embodiment of the present invention, the methods forsynthesising a molecule linked to a single stranded identifieroligonucleotide is targeted to a target compound known to be involved ininduction of apoptosis, cell death loss of cell division or decreasedcell growth.

Targets can include e.g. known proteins such as Abl, Src, Ras, andothers, which lead to abnormal cell growth in certain cells or thedevelopment of micro-metastases. Thus, in one embodiment, bioactivespecies obtainable by the methods of the invention are introduced intocancer cells to select for bioactive species which reverse or correct acancer condition. One of the signal features of oncogene activity incells is the loss of contact inhibition and the ability to grow insoft-agar. When e.g. Abl, Src, or Ras are expressed 3T3 cells andsubjected to puromycin selection, all of the 3T3 cells hyper-transformand detach from the plate. The cells can be removed by washing withfresh medium. This can serve as the basis of a screen, since cells whichexpress a bioactive species having anti-cancer activity will remainattached to the plate and form colonies.

Similarly, the growth and/or spread of certain tumor types is enhancedby stimulatory responses from growth factors and cytokines (PDGF, EGF,Heregulin, and others) which bind to receptors on the surfaces ofspecific tumors. In one embodiment, the bioactive species obtainable bythe methods of the invention are used to inhibit or stop tumor growthand/or spread selecting bioactive species capable of blocking theability of the growth factor or cytokine to stimulate the tumor cell.The introduction of bioactive species obtainable by the methods of thepresent invention into specific tumor cells with the addition of thegrowth factor or cytokine, followed by selection of bioactive specieswhich block the binding, signaling, phenotypic and/or functionalresponses of these tumor cells to the growth factor or cytokine inquestion, represent one embodiment of the present invention.

Similarly, the spread of cancer cells (invasion and metastasis) is asignificant problem limiting the success of cancer therapies. Theability to inhibit the invasion and/or migration of specific tumor cellswould be a significant advance in the therapy of cancer. Tumor cellsknown to have a high metastatic potential (for example, melanoma, lungcell carcinoma, breast and ovarian carcinoma) can have bioactive speciesobtainable by the methods of the present invention introduced into them,and bioactive species selected which in a migration or invasion assay,inhibit the migration and/or invasion of specific tumor cells.Particular applications for inhibition of the metastatic phenotype,which could allow a more specific inhibition of metastasis, include thepolypeptide encoded by the metastasis suppressor gene NM23, which codesfor a dinucleoside diphosphate kinase. Thus, bioactive species acting asactivators of this gene could block metastasis. Many oncogene productsalso enhance metastasis.

Bioactive species which inactivate or counteract gene products encodedby mutated RAS oncogenes, v-MOS, v-RAF, A-RAF, v-SRC, v-FES, and v-FMSwould also act as anti-metastatics. Bioactive species obtainable by theinvention which act intracellularly to block the release of combinationsof proteases required for invasion, such as the matrix metalloproteasesand urokinase, could also be effective antimetastatics.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention are introduced into tumor cells known to haveinactivated tumor suppressors, and successful reversal e.g. bycompensation of suppression of the suppressor can be screened for e.g.by restoration of a normal phenotype. A major example is the reversal ofp53-inactivating mutations, which are present in 50% or more of allcancers. Since p53's actions are complex and involve its action as atranscription factor, there are probably numerous potential ways a smallmolecule bioactive species could reverse the mutation. One example couldbe e.g. to increase the activity of the cyclin-dependent kinasep21CIP1NVAF1. To be useful such reversal would have to work for many ofthe different known p53 mutations. It is possible to screen for one ormore small molecules possessing the above-cited activities.

In another embodiment, the methods of the present invention forsynthesising and selecting small molecule bioactive species are usefulin various cardiovascular applications. In one embodiment,cardiomyocytes can be screened for the prevention of cell damage ordeath in the presence of normally injurious conditions, including, butnot limited to, the presence of toxic drugs (particularlychemo-therapeutic drugs), for example, to prevent heart failurefollowing treatment with adriamycin; anoxia, for example in the settingof coronary artery occlusion; and autoimmune cellular damage by attackfrom activated lymphoid cells (for example as seen in post viralmyocarditis and lupus). Candidate bioactive species are inserted intocardiomyocytes, the cells are subjected to the insult. It is possible toscreen for bioactive species are selected that prevent any or all of:apoptosis; membrane depolarization (i.e. decrease arrythmogenicpotential of insult); cell swelling; or leakage of specificintracellular ions, second messengers and activating molecules (forexample, arachidonic acid and/or lysophosphatidic acid).

In yet another embodiment, the bioactive species obtainable by themethods of the present invention are used to screen for diminishedarrhythmia potential in cardiomyocytes. The screens comprise theintroduction of the candidate bioactive species, followed by theapplication of arrythmogenic insults, with screening for bioactivespecies that block specific depolarization of cell membrane. This can bedetected using patch clamps, or via fluorescence techniques). Similarly,channel activity (for example, potassium and chloride channels) incardiomyocytes could be regulated using the bioactive species obtainableby the methods of the present invention in order to enhancecontractility and prevent or diminish arrhythmias.

In yet another embodiment, the bioactive species obtainable by themethods of the present invention are used to screen for enhancedcontractile properties of cardiomyocytes and diminish heart failurepotential. The introduction of the bioactive species obtainable by themethods of the present invention followed by measuring the rate ofchange of myosin polymerization/depolymerization using fluorescenttechniques can be done. It is possible to screen for bioactive specieswhich increase the rate of change of this phenomenon can result in agreater contractile response of the entire myocardium, similar to theeffect seen with digitalis.

In a still further embodiment, selected bioactive species obtainable bythe methods of the present invention can be useful for identifyingagents involved in the regulation of intracellular and sarcolemmalcalcium cycling in cardiomyocytes in order to prevent arrhythmias. It ispossible to screen for bioactive species which regulate sodium-calciumexchange, sodium proton pump function, and regulation of calcium-ATPaseactivity in human or animal cells.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention are useful for identifying agents that diminishembolic phenomena in arteries and arterioles leading to strokes (andother occlusive events leading to kidney failure and limb ischemia) andangina precipitating a myocardial infarct are selected. For example, itis possible to screen for bioactive species which will diminish theadhesion of platelets and leukocytes, and thus diminish the occlusionevents.

Adhesion in this setting can be inhibited by the bioactive speciesobtainable by the methods of the present invention once such bioactivespecies are inserted into endothelial cells (quiescent cells, oractivated by cytokines, i.e. IL-1, and growth factors, i.e. PDGF I EGF)and then screened for either: 1) downregulation of adhesion moleculeexpression on the surface of the endothelial cells (binding assay); 2)blocking of adhesion molecule activation on the surface of these cells(signaling assay); or 3) releasing in an autocrine manner biologicalmolecules including peptides that block receptor binding to the cognatereceptor on the adhering cell.

Embolic phenomena can also be addressed by activating proteolyticenzymes on the cell surfaces of endothelial cells, and thus releasingactive enzyme which can digest blood clots. Thus, the bioactive speciesobtainable by the methods of the present invention can be introducedinto endothelial cells, followed by standard fluorogenic assays, whichwill allow monitoring of proteolytic activity on the cell surfacetowards a known substrate. Bioactive species can then be selected whichactivate specific enzymes towards specific substrates.

In one embodiment, arterial inflammation in the setting of vasculitisand post-infarction can be regulated by decreasing the chemotacticresponses of leukocytes and mononuclear leukocytes. This can beaccomplished by blocking chemotactic receptors and their respondingpathways on these cells. Candidate bioactive species can thus beinserted into these cells, and one can screen for inhibition of thechemotactic response to diverse chemokines (for example, to the IL-8family of chemokines, RANTES) in cell migration assays.

In yet another embodiment, arterial restenosis following coronaryangioplasty can be controlled by regulating the proliferation ofvascular intimal cells and capillary and/or arterial endothelial cells.Candidate bioactive species can be inserted into these cell types andtheir proliferation in response to specific stimuli can be monitored. Itis possible to screen for bioactive species which are capable ofblocking the expression or function of c-myc and other oncogene productsin smooth muscle cells to stop their proliferation. It would also bepossible to introduce the bioactive species obtainable by the methods ofthe present invention into vascular smooth muscle cells and to screenfor bioactive species which can selectively induce apoptosis.

Application of small molecule bioactive species may require targeteddrug delivery; this is available e.g. with stents, hydrogel coatings,and infusion-based catheter systems. Bioactive species which downregulate endothelin-1A receptors or which block the release of thepotent vasoconstrictor and vascular smooth muscle cell mitogenendothelin-1 may also be candidates for therapeutics. Accordingly, it ispossible to screen for bioactive species which can inhibit growth ofthese cells, or which prevent the adhesion of other cells in thecirculation known to release autocrine growth factors, such as platelets(PDGF) and mononuclear leukocytes.

The control of capillary and blood vessel growth is an important goal inorder to promote increased blood flow to ischemic areas (growth), or tocut-off the blood supply (angiogenesis inhibition) of tumors. Candidatebioactive species can be inserted into capillary endothelial cells andthe growth of such cells can be monitored. Stimuli such as low oxygentension and varying degrees of angiogenic factors can regulate theresponses, and one can screen for bioactive species which can producethe appropriate phenotype. Screening for bioactive species capable ofacting as antagonisms of vascular endothelial cell growth factor,important in angiogenesis, would also be useful.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention are useful in screening for decreases inatherosclerosis producing mechanisms to find biological molecules thatregulate LDL and HDL metabolism. Candidate bioactive species can beinserted into the appropriate cells (including hepatocytes, mononuclearleukocytes, endothelial cells) and one can screen for bioactive specieswhich lead to a decreased release of LDL or diminished synthesis of LDL,or conversely to an increased release of HDL or enhanced synthesis ofHDL. It is also possible to screen for bioactive species which decreasesthe production of oxidized LDL, which has been implicated inatherosclerosis and isolated from atherosclerotic lesions. This couldoccur e.g. by activating reducing systems or enzymes, or blocking theactivity or production of enzymes implicated in production of oxidizedLDL, such as 15-lipoxygenase in macrophages.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention are used in screens to regulate obesity via thecontrol of food intake mechanisms or diminishing the responses ofreceptor signaling pathways that regulate metabolism. One can screen forbioactive species that regulate or inhibit the responses of neuropeptideY (NPY), cholecystokinin and galanin receptors. Candidate bioactivespecies can be inserted into cells that have these receptors cloned intothem, and one can screen for bioactive species which block the signalingresponses to galanin and NPY. In a similar manner, one can screen forbioactive species which regulate the leptin receptor.

In a still further embodiment, bioactive species obtainable by themethods of the present invention can be used in screens in neurobiologyapplications. Candidate bioactive species can be used for screening foranti-apoptotics for preservation of neuronal function and prevention ofneuronal death. Initial screens would be done in cell culture. Oneapplication would include prevention of neuronal death, by apoptosis, incerebral ischemia resulting from stroke. Apoptosis is known to beblocked by neuronal apoptosis inhibitory polypeptide (NAIP); screens forits upregulation, or effecting any coupled step could yield bioactivespecies which selectively block neuronal apoptosis. Other applicationsinclude neurodegenerative diseases such as Alzheimer's disease andHuntington's disease.

In another embodiment, bioactive species obtainable by the methods ofthe present invention can be used in screens in bone biologyapplications. Osteoclasts are known to play a key role in boneremodeling by breaking down “old” bone, so that osteoblasts can lay down“new” bone. In osteoporosis one has an imbalance of this process. Ascreen for osteoclast overactivity can be set up by introducingcandidate bioactive species to these cells, and then screening forbioactive species that produce: 1) a diminished processing of collagenby these cells; 2) decreased pit formation on bone chips; and 3)decreased release of calcium from bone fragments.

The bioactive species obtainable by the methods of the present inventioncan also be used in screens for agonists of bone morphogenic biologicalmolecules and hormone mimetics to stimulate, regulate, or enhance newbone formation (in a manner similar to parathyroid hormone andcalcitonin, for example). These have use in osteoporosis, for poorlyhealing fractures, and to accelerate the rate of healing of newfractures. Furthermore, cell lines of connective tissue origin can betreated with candidate bioactive species and screened for their growth,proliferation, collagen stimulating activity, and/or prolineincorporating ability on the target osteoblasts. Alternatively,candidate bioactive species can be screened for their ability toincrease production of collagen or bone.

In one embodiment, bioactive species obtainable by the methods of thepresent invention can be screened for activities which are useful invarious skin biology applications. Keratinocyte responses to a varietyof stimuli may result in psoriasis, a proliferative change in thesecells. Candidate bioactive species can be inserted into cells removedfrom active psoriatic plaques, and one can screen for bioactive specieswhich decrease the rate of growth of these cells.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention can be screened for activities which are useful inthe regulation or inhibition of keloid formation (i.e. excessivescarring). Candidate bioactive species can be introduced into skinconnective tissue cells isolated from individuals with this condition,and one can screen for bioactive species that decrease proliferation,collagen formation, or proline incorporation. Results from this work canbe extended to treat the excessive scarring that also occurs in burnpatients. If a common bioactive species motif is found in the context ofthe keloid work, then it can be tested if this motif can be used widelyin a topical manner to diminish scarring post burn.

Similarly, wound healing for diabetic ulcers and other chronic “failureto heal” conditions in the skin and extremities can be regulated byproviding additional growth signals to cells which populate the skin anddermal layers. Growth factor mimetics may in fact be very useful forthis condition. Candidate bioactive species can be inserted into skinconnective tissue cells, and one can screen for bioactive species whichpromote the growth of these cells under “harsh” conditions, such as lowoxygen tension, low pH, and the presence of inflammatory mediators.

Cosmeceutical applications of the present invention include the controlof melanin production in skin melanocytes. A naturally occurringpeptide, arbutin, is a tyrosine hydroxylase inhibitor, a key enzyme inthe synthesis of melanin. Candidate bioactive species can be introducedinto melanocytes and known stimuli that increase the synthesis ofmelanin applied to the cells. One can screen for bioactive species whichinhibit the synthesis of melanin under these conditions.

In one embodiment, one can screen for activities of bioactive speciesobtainable by the methods of the present invention which are useful inendocrinology applications. The methods of the present invention and thebioactive species thus obtained can be applied broadly to any endocrine,growth factor, cytokine or chemokine network which involves a signalingpeptide or polypeptide that acts in either an endocrine, paracrine orautocrine manner that binds or dimerizes a receptor and activates asignaling cascade that results in a known phenotypic or functionaloutcome. One can screen for bioactive species which either mimics adesired hormone (i.e., insulin, leptin, calcitonin, PDGF, EGF, EPO,GMCSF, IL1-17, mimetics) or inhibits its action by either blocking therelease of the hormone, blocking its binding to a specific receptor orcarrier polypeptide (for example, CRF binding polypeptide), orinhibiting the intracellular responses of the specific target cells tothat hormone. It is also possible to screen for bioactive species whichincrease the expression or release of hormones from cells which normallyproduce them. This would have broad applications in conditions ofhormonal deficiency.

In one embodiment, one can screen for activities of bioactive speciesobtainable by the methods of the present invention which are useful ininfectious disease applications. Viral latency (herpes viruses such asCMV, EBV, HBV, and other viruses such as HIV) and their reactivation area significant problem, particularly in immunosuppressed patients(patients with AIDS and transplant patients). The ability to block thereactivation and spread of these viruses is an important goal. Celllines known to harbor or be susceptible to latent viral infection can beinfected with the specific virus, and then stimuli applied to thesecells which have been shown to lead to reactivation and viralreplication. This can be followed by measuring viral titers in themedium and scoring cells for phenotypic changes. Candidate bioactivespecies can then be introduced into these cells under the aboveconditions, and one can screen for bioactive species which block ordiminish the growth and/or release of the virus. As withchemotherapeutics, these experiments can also be done in combinationwith drugs which are only partially effective towards this outcome, andone can screen for bioactive species which enhance the virucidal effectof these drugs.

One example of many is the ability to block HIV-1 infection. HIV-1requires CD4 and a co-receptor which can be one of several seventransmembrane G-polypeptide coupled receptors. In the case of theinfection of macrophages, CCR-5 is the required coreceptor, and there isstrong evidence that a block on CCR-5 will result in resistance to HIV-1infection. There are two lines of evidence for this statement.

First, it is known that the natural ligands for CCR-5, the CC chemokinesRANTES, MIPIa and MIPIb are responsible for CD8+ mediated resistance toHIV. Second, individuals homozygous for a mutant allele of CCR-5 arecompletely resistant to HIV infection. Accordingly, one can screen foractivities of bioactive species obtainable by the methods of the presentinvention which are inhibitory for CCR-5/HIV interaction.

Viruses are known to enter cells using specific receptors to bind tocells (for example, HIV uses CD4, coronavirus uses CD13, murine leukemiavirus uses transport polypeptide, and measles virus uses CD44) and tofuse with cells (HIV uses chemokine receptor). Candidate bioactivespecies can be introduced into target cells known to be permissive tothese viruses, and one can screen for bioactive species which block theability of these viruses to bind to and fuse with specific target cells.

In one embodiment, one can screen for activities of bioactive speciesobtainable by the methods of the present invention which haveapplications in the area of infectious organisms. Intracellularorganisms such as mycobacteria, listeria, salmonella, pneumocystis,yersinia, leishmania, T. cruzi, can persist and replicate within cells,and become active in immunosuppressed patients. There are currentlydrugs on the market and in development which are either only partiallyeffective or ineffective against these organisms. Candidate bioactivespecies can be inserted into specific cells infected with theseorganisms (pre- or post-infection), and one can screen for bioactivespecies which promote the intracellular destruction of these organismsin a manner analogous to intracellular “antibiotic bioactive species”similar to magainins. In addition, one can screen for bioactive specieswhich enhance the cidal properties of drugs already under investigationwhich have insufficient potency by themselves, but, when combined withone or more bioactive species obtainable by the methods of the presentinvention, are dramatically more potent through a synergistic mechanismor otherwise. One can screen for bioactive species which alter themetabolism of these intracellular organisms, in such a way as toterminate their intracellular life cycle by inhibiting a key organismalevent.

Antibiotic drugs that are widely used have certain dose dependent,tissue specific toxicities. For example renal toxicity is seen with theuse of gentamicin, tobramycin, and amphotericin; hepatotoxicity is seenwith the use of INH and rifampin; bone marrow toxicity is seen withchloramphenicol; and platelet toxicity is seen with ticarcillin, etc.These toxicities limit their use. One can introduce candidate bioactivespecies into the specific cell types where specific changes leading tocellular damage or apoptosis by the antibiotics are produced, and onecan screen for bioactive species which confer protection, when thesecells are treated with these specific antibiotics.

Furthermore, the present invention finds use in screening for bioactivespecies that block antibiotic transport mechanisms. The rapid secretionfrom the blood stream of certain antibiotics limits their usefulness.For example penicillins are rapidly secreted by certain transportmechanisms in the kidney and choroid plexus in the brain. Probenecid isknown to block this transport and increase serum and tissue levels.Candidate agents can be introduced into specific cells derived fromkidney cells and cells of the choroid plexus known to have activetransport mechanisms for antibiotics. One can then screen for bioactivespecies which block the active transport of specific antibiotics andthus extend the serum halflife of these drugs.

In one embodiment bioactive species obtainable by the methods of thepresent invention are useful in drug toxicities and drug resistanceapplications. Drug toxicity is a significant clinical problem. This maymanifest itself as specific tissue or cell damage with the result thatthe drug's effectiveness is limited. Examples include myeloablation inhigh dose cancer chemotherapy, damage to epithelial cells lining theairway and gut, and hair loss.

Specific examples include adriamycin induced cardiomyocyte death,cisplatinin-induced kidney toxicity, vincristine-induced gut motilitydisorders, and cyclosporin-induced kidney damage. Candidate bioactivespecies can be introduced into specific cell types with characteristicdrug-induced phenotypic or functional responses, in the presence of thedrugs, and one can screen for bioactive agents which reverse or protectthe specific cell type against the toxic changes when exposed to thedrug. These effects may manifest as blocking the drug induced apoptosisof the cell of interest, thus initial screens will be for survival ofthe cells in the presence of high levels of drugs or combinations ofdrugs used in combination chemotherapy.

Drug toxicity can be due to a specific metabolite produced in the liveror kidney which is highly toxic to specific cells, or due to druginteractions in the liver which block or enhance the metabolism of anadministered drug. Candidate bioactive species can be introduced intoliver or kidney cells following the exposure of these cells to the drugknown to produce the toxic metabolite. One can screen for bioactivespecies which alter how the liver or kidney cells metabolize the drug,and for bioactive species which prevent the generation of a specifictoxic metabolite. The generation of the metabolite can be followed bymass spectrometry, and phenotypic changes can be assessed by microscopy.Such a screen can also be done in cultured hepatocytes, cocultured withreadout cells which are specifically sensitive to the toxic metabolite.Applications include reversible (to limit toxicity) inhibitors ofenzymes involved in drug metabolism.

Multiple drug resistance, and hence tumor cell selection, outgrowth, andrelapse, leads to morbidity and mortality in cancer patients. Candidatebioactive species can be introduced into tumor cell lines (primary andcultured) that have demonstrated specific or multiple drug resistance.One can then screen for bioactive species which confer drug sensitivitywhen the cells are exposed to the drug of interest, or to drugs used incombination chemotherapy. The readout can be the onset of apoptosis inthese cells, membrane permeability changes, the release of intracellularions and fluorescent markers. The cells in which multidrug resistanceinvolves membrane transporters can be preloaded with fluorescenttransporter substrates, and selection carried out for bioactive specieswhich block the normal efflux of fluorescent drug from these cells.Candidate bioactive species are particularly suited to screening forbioactive species which reverse poorly characterized or recentlydiscovered intracellular mechanisms of resistance or mechanisms forwhich few or no chemosensitizers currently exist, such as mechanismsinvolving LRP (lung resistance polypeptide). This polypeptide has beenimplicated in multidrug resistance in ovarian carcinoma, metastaticmalignant melanoma, and acute myeloid leukemia. Particularly interestingexamples include screening for agents which reverse more than oneimportant resistance mechanism in a single cell, which occurs in asubset of the most drug resistant cells, which are also importanttargets. Applications would include screening for inhibitors of both MRP(multidrug resistance related polypeptide) and LRP for treatment ofresistant cells in metastatic melanoma, for inhibitors of bothp-glycopolypeptide and LRP in acute myeloid leukemia, and for inhibition(by any mechanism) of all three polybioactive species for treatingpan-resistant cells.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention are useful in improving the performance ofexisting or developmental drugs. First pass metabolism of orallyadministered drugs limits their oral bioavailability, and can result indiminished efficacy as well as the need to administer more drug for adesired effect. Reversible inhibitors of enzymes involved in first passmetabolism may thus be a useful adjunct enhancing the efficacy of thesedrugs. First pass metabolism occurs in the liver, thus inhibitors of thecorresponding catabolic enzymes may enhance the effect of the cognatedrugs.

Reversible inhibitors would be delivered at the same time as, orslightly before, the drug of interest. Screening of candidate bioactivespecies in hepatocytes for inhibitors (by any mechanism, such aspolypeptide down regulation as well as a direct inhibition of activity)of particularly problematical isozymes would be of interest. Theseinclude the CYP3A4 isozymes of cytochrome P450, which are involved inthe first pass metabolism of the anti-HIV drugs saquinavir andindinavir. Other applications could include reversible inhibitors ofUDP-glucuronyltransferases, sulfotransferases, N-acetyltransferases,epoxide hydrolases, and glutathione 5-transferases, depending on thedrug. Screens would be done in cultured hepatocytes or liver microsomes,and could involve antibodies recognizing the specific modificationperformed in the liver, or cocultured readout cells, if the metabolitehad a different bioactivity than the untransformed drug.

The enzymes modifying the drug would not necessarily have to be known,if screening was for lack of alteration of the drug.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention are useful in immunobiology, inflammation, andallergic response applications. Selective regulation of T lymphocyteresponses is a desired goal in order to modulate immune-mediateddiseases in a specific manner. Candidate bioactive species can beintroduced into specific T cell subsets (TH1, TH2, CD4+, CD8+, andothers) and the responses which characterize those subsets (cytokinegeneration, cytotoxicity, proliferation in response to antigen beingpresented by a mononuclear leukocyte, and others) modified by members ofthe library. One can screen for activities of bioactive speciesobtainable by the methods of the present invention which increase ordiminish the known T cell subset physiologic response. This approachwill be useful in any number of conditions, including: 1) autoimmunediseases where one wants to induce a tolerant state (select a peptidethat inhibits T cell subset from recognizing a self-antigen bearingcell); 2) allergic diseases where one wants to decrease the stimulationof IgE producing cells (select peptide which blocks release from T cellsubsets of specific Cell stimulating cytokines which induce switch toIgE production); 3) in transplant patients where one wants to induceselective immunosuppression (select peptide that diminishesproliferative responses of host T cells to foreign antigens); 4) inlymphoproliferative states where one wants to inhibit the growth orsensitize a specific T cell tumor to chemotherapy and/or radiation; 5)in tumor surveillance where one wants to inhibit the killing ofcytotoxic T cells by Fas ligand bearing tumor cells; and 5) in T cellmediated inflammatory diseases such as Rheumatoid arthritis, Connectivetissue diseases (SLE), Multiple sclerosis, and inflammatory boweldisease, where one wants to inhibit the proliferation of disease-causingT cells (promote their selective apoptosis) and the resulting selectivedestruction of target tissues (cartilage, connective tissue,oligodendrocytes, gut endothelial cells, respectively).

Regulation of B cell responses will permit a more selective modulationof the type and amount of immunoglobulin made and secreted by specific Bcell subsets. Candidate bioactive species can be introduced into B cellsand one can screen for activities of bioactive species which inhibit therelease and synthesis of a specific immunoglobulin. This can be usefulin autoimmune diseases characterized by the overproduction of autoantibodies and the production of allergy causing antibodies, such asIgE. One can also screen for bioactive species which inhibit or enhancethe binding of a specific immunoglobulin subclass to a specific antigeneither foreign of self. Finally, one can screen for bioactive specieswhich inhibit the binding of a specific immunoglobulin subclass to itsreceptor on specific cell types.

Similarly, one can screen for bioactive agents which affect cytokineproduction, generally by using two cell systems. For example, cytokineproduction from macrophages, monocytes, etc. can be evaluated.Similarly, one can screen for bioactive species which mimic cytokines,for example erythropoetin and IL1-17, or for bioactive species that bindcytokines such as TNF-alpha, before they bind their receptor.

Antigen processing by mononuclear leukocytes (ML) is an important earlystep in the immune system's ability to recognize and eliminate foreignpolybioactive species. Candidate bioactive species can be introducedinto ML cell lines and one can screen for bioactive species which alterthe intracellular processing of foreign bioactive species and sequenceof the foreign peptide that is presented to T cells by MLs on their cellsurface in the context of Class II MHC. One can look for members of alibrary of bioactive species which enhance immune responses of aparticular T cell subset (for example, the peptide would in fact work asa vaccine), or look for a bioactive species library member that bindsmore tightly to MHC, thus displacing naturally occurring bioactivespecies, but nonetheless the bioactive species would be less immunogenic(less stimulatory to a specific T cell clone). Such bioactive specieswould in fact induce immune tolerance and/or diminish immune responsesto foreign agents, such as polypeptides. This approach could be used intransplantation, autoimmune diseases, and allergic diseases.

The release of inflammatory mediators (cytokines, leukotrienes,prostaglandins, platelet activating factor, histamine, neurobioactivespecies, and other peptide and lipid mediators) is a key element inmaintaining and amplifying aberrant immune responses. Candidatebioactive species can be introduced into MLs, mast cells, eosinophils,and other cells participating in a specific inflammatory response, andone can screen for bioactive species which inhibit the synthesis,release and binding to the cognate receptor of each of these types ofmediators.

In one embodiment, the bioactive species obtainable by the methods ofthe present invention are useful in biotechnology applications. Randombioactive species displayed on the surface of circulating cells can beused as tools to identify organ, tissue, and cell specific targetingsequences. Any cell introduced into the bloodstream of an animalexpressing a library targeted to the cell surface can be selected forspecific organ and tissue targeting. The bioactive species identified inthis way can then be coupled to an antibody, enzyme, drug, imaging agentor substance for which organ targeting is desired.

Other bioactive species for which screens can be set up include: 1)bioactive species which block e.g. the activity of transcriptionfactors, using cell lines with reporter genes; 2) bioactive specieswhich block the interaction of two known biological molecules in cells,using the absence of normal cellular functions, the mammalian two-hybridsystem or fluorescence resonance energy transfer mechanisms fordetection.

Enrichment

The present invention also relates to a method for determining theidentity of a chemical entity having a preselected property, comprisingthe steps of:

i) generating a tagged library of chemical entities by appending uniqueidentifier tags to chemical entities,ii) subjecting the library to a condition, wherein a chemical entity ora subset of chemical entities having a predetermined property ispartitioned from the remainder of the library,iii) recovering an anti-tag from the partitioned library, said anti-tagbeing capable of interacting with the unique identifier tag in aspecific manner, andiv) identifying the chemical entity/ies having a preselected function bydecoding the anti-tag.

The tag is appended the chemical entity by a suitable process. Notably,each chemical entity is appended a tag by a reaction involving achemical reaction between a reactive group of the chemical entity and areactive group of the tag, such as method A and B of the selectionsection. The attachment of the chemical entity can be directly orthrough a bridging molecule part. The molecule part can be any suitablechemical structure able to connect the chemical entity to the tag.

The anti-tag has the ability to interact with the unique identifier tagin a specific manner. The chemical structure of the anti-tag is to alarge extent dependant on the choice of unique tag. As an example, ifthe unique tag is chosen as an antibody, the anti-tag is selected as theepitope able to associate with the antibody. In general, it is preferredto use an anti-tag comprising a sequence of nucleotides complementary toa unique identifier tag.

The method can be performed without amplification in certainembodiments. However, when larger bioactive species are intended, it isin general preferred to use an anti-tag which is amplifiable. Anti-tagscomprising a sequence of nucleotides can be amplified using standardtechniques like PCR.

In the event the tag as well as the anti-tag is a sequence of nucleicacids, a tag:anti-tag hybrid can be formed prior to the subjecting thelibrary to partitioning conditions or subsequent to the partitioningstep. In some embodiments of the invention it is preferred to form thetag:anti-tag hybrid prior to the partition step in order to make theappended nucleotide sequence inert relative to the system as it is wellknown that certain sequences of nucleotides can bind to a target orcatalyse a chemical reaction.

The oligonucleotide anti-tag can be formed in a variety of ways. In oneembodiment of the invention, the anti-tag is formed as an enzymaticextension reaction. The extension comprises the initial annealing of aprimer to the unique identifier tag and subsequent extension of theprimer using a polymerase and dNTPs. Other types of extension reactionsmay also be contemplated. As an example ligases can be used to createthe primer starting from di- or trinucleotide substrates and theextension can be performed using a suitable polymerase.

It can be desirable to recover the anti-tag at various steps during theprocess. To this end it is preferred in some aspects of the invention toprovide the primer provided with a chemical entity capable of binding toa suitable affinity partner. An arsenal of different chemical entitiesand affinity partners are available to the skilled person in the art.The most widely used chemical entity is biotin, which in general arealso preferred according to the present invention. Biotin binds to theaffinity partner streptavidin or avidin. A standard technique in thelaboratory is to recover a biochemical entity having attached a biotinusing a solid phase covered with streptavidin. Suitably, the solid phaseis a bead which can be separated from the liquid after the bindingaction by rotation or a magnetic field in case the solid bead comprisesmagnetic particles.

In other aspects of the present invention, the anti-tag is provided as aseparate oligonucleotide. The separate oligonucleotide can be producedusing standard amidite synthesis strategies or can be provided usingother useful methods. It is in general preferred to provide theoligonucleotide by synthesis, at least in part, because the biotinamidite is easily incorporated in a nascent oligonucleotide strand.Following the addition of an oligonucleotide anti-tag to a liquidcomprising chemical entities tagged with complementing oligonucleotidetags a double stranded library is formed as a hybridisation productbetween the unique identifier tag and the anti-tag oligonucleotide.

As mentioned above, the anti-tag oligonucleotide can be provided with achemical entity, such as biotin, capable of binding to an affinitypartner, such as streptavidin or avidin.

Following the addition of the anti-tag oligonucleotides to the taggedchemical entities, some of the oligonucleotides present in the media maynot find a partner. In one embodiment of the invention it is preferredthat oligonucleotides not hybridised to a cognate unique identifierand/or anti-tag are transformed into a double helix. In other aspects ofthe invention single stranded oligonucleotides are degraded prior tostep ii) to avoid unintended interference.

The chemical entity can be used to purify the library prior to orsubsequent to the partitioning step. In some embodiments of theinvention, the purification step is performed prior to the partitioningstep to reduce the noise of the system. In another aspect the chemicalentity is used to purify the partitioned library subsequent to step ii)in order to recover a double stranded product which can be amplified.

The library is subjected to a condition in order to select chemicalentities having a property which is responsive to this condition. Thecondition may involve the exposure of the library to a target andpartitioning the chemical entities having an affinity towards thistarget. Another condition could be subjecting the library to a substrateand partitioning chemical entities having a catalytical activityrelative to this substrate.

The anti-tag can be formed subsequent to the partitioning step. In anaspect of the invention, the single stranded nucleotide serving as a tagis made double stranded while the chemical entity is attached to thetarget of an affinity partitioning. Optionally, in a repeatedtemperature cycle, a plurality of anti-tags can be formed as extensionproducts using the tag as template. In another aspect of the invention,the chemical entity bearing the single stranded oligonucleotide isdetached from the target and a complementing anti-tag is subsequentlyprepared.

In the event the anti-tag comprises a chemical entity, this chemicalentity can be used to purify the partitioned library. The recovery ofthe anti-tag is then performed by melting off said anti-tag from apartitioned double stranded library. Optionally, the amount of anti-tagscan be multiplied by conventional amplification techniques, such as PCR.

The method according to the invention can be performed using a singlepartitioning step. Usually, it is preferred, however, to use more thanone partitioning step in order to select the candidate having thedesired properties from a large library. Thus, the recovered anti-tagscan be mixed with the initial library or a subset thereof and the stepsof partitioning (step ii)) and recovery (step iii)) may is repeated adesired number of times. Optionally, single stranded moieties in themixture can be degraded or removed or made inert as described above.

Generally, the partitioned library obtained in step ii) is subjected toone or more further contacting steps using increasing stringencyconditions. The stringency conditions can be increased by increasing thetemperature, salt concentration, acidity, alkalinity, etc.

In one embodiment of the invention, the partitioned library is notsubjected to intermediate process steps prior to a repeated contactingstep. Especially, the partitioned library is not subjected tointermediate amplification of the anti-tag. This embodiment can be ofadvantage when relatively small bioactive species are used.

The method of the invention terminates with a decoding step, that is astep in which the identity of the chemical entity or entities aredeciphered by an analysis of the anti-tag. When the anti-tag is anoligonucleotide, the decoding step iv) can be performed by sequencing ananti-tag nucleotide. Various methods for sequencing are apparent for theskilled person, including the use of cloning and exposure to amicroarray.

The tags contain recognizing groups such as e.g. nucleotide sequence(s),epitope(s) a.o. The tags carries information of the entity to which itis attached, such as e.g. entity structure, mass, spatial position(plate information) etc. The tags can be composed of monoclonalantibodies, bioactive species, proteins, oligonucleotides, DNA, RNA,LNA, PNA, natural bioactive species, unnatural bioactive species,polymeric or oligomeric hydrazino aryl and alkyl carboxylic acids,polymeric or oligomeric aminoxy aryl and alkyl carboxylic acids,peptoids, other natural polymers or oligomers, unnatural polymers(molecular weight >1000 Da) or oligomers (molecular weight <1000 Da),small non-polymeric molecules (molecular weight <1000 Da) or largenon-polymeric molecules (molecular weight >1000 Da).

In one embodiment, entities consist of small non-polymeric molecules(molecular weight <1000 Da). Small molecules are generally the compoundsof interest in the quest for drug oral candidates. Especially, smallmolecules not occurring in Nature are of interest in the drug discoveryprocess and in one embodiment of the present invention the method aredesigned to select a oral drug candidate. A variety of drug candidatebioactive species are available on the market. The drug candidates ofthe library usually comprise a reactive group or a group which can bealtered into a reactive group. In one preferred aspect of the presentinvention each of the members of the drug candidate library is appendeda nucleic acid tag via said reactive group of the library member and areactive group on the nucleic acid. Preferably, the nucleic acid is anoligonucleotide.

In another aspect of the invention, entities consist of largenon-polymeric molecules (molecular weight >1000 Da). In still anotherembodiment, entities consist of polymeric molecules.

The tags and anti-tags can be composed of RNA linked to monoclonalantibodies, proteins, LNA, PNA, natural polybioactive species, unnaturalpolybioactive species, polymeric or oligomeric hydrazino aryl or alkylcarboxylic acids, polymeric or oligomeric aminoxy aryl or alkylcarboxylic acids, other natural polymers or oligomers, unnaturalpolymers (molecular weight >1000 Da) or oligomers (molecular weight<1000 Da), small non-polymeric molecules (molecular weight <1000 Da) orlarge non-polymeric molecules (molecular weight >1000 Da).

Alternatively, anti-tags can be composed of DNA linked to monoclonalantibodies, proteins, LNA, PNA, natural polybioactive species, unnaturalpolybioactive species, polymeric or oligomeric hydrazino aryl or alkylcarboxylic acids, polymeric or oligomeric aminoxy aryl or alkylcarboxylic acids, other natural polymers or oligomers, unnaturalpolymers (molecular weight >1000 Da) or oligomers (molecular weight<1000 Da), small non-polymeric molecules (molecular weight <1000 Da) orlarge non-polymeric molecules (molecular weight >1000 Da).Alternatively, anti-tags are just composed of oligonucleotides, DNA orRNA. In a embodiment, anti-tags are composed of DNA. In anotherembodiment anti-tags are composed of RNA.

Anti-tags which are linked to DNA or RNA are also encoded by the DNA/RNAlinked to them, e.g. phage displayed or polysome displayed antibodies,bioactive species or proteins, and via DNA-templated synthesis ofanti-tags, where the DNA encode the synthesis of the anti-tag, which islinked to its DNA during its synthesis.

Each chemical compound or group of compounds can be associated with atag through formation of a covalent or non-covalent bond. For covalentbond formation, tagging may involve, but is not limited to, theformation of a cycloaddition product, an alkylation product, anarylation product, an acylation product, an amide bond, a carboxylicester bond, a sulfonamide bond, a disulfide bond, an S-alkyl bond, anNR-alkyl bond, an O-alkyl bond, an aryl-vinyl bond, an alkyne-vinylbond, an oxime bond, an imine bond, a bicyclic product, a trizole, ahexene, a 7-Oxa-bicyclo[2.2.1]hept-2-ene derivative, a7-Aza-bicyclo[2.2.1]hept-2-ene derivative or a7-Methyl-7-aza-bicyclo[2.2.1]hept-2-ene. Non-covalent bonds may involve,but are not limited to, attachment via e.g. hydrogen bonding, van derWaals interactions, pi-stacking or through hybridization. Hybridizationcan be between complementary strands of DNA, RNA, PNA or LNA or mixturesthereof. In such case both the tag and the chemical compound carriessuch a strand complementary to each other. The tagged entity, compoundor mixture of compounds can be transformed into a new tagged entity,e.g. by transformation of the entity or by transformation of the tag.The transformation can be caused by either chemical or physicaltransformations such e.g. addition of reagents (e.g. oxidizing orreducing agents, pH adjustment a.o.) or subjection to UV-irradiation orheat.

The complex between tags and anti-tags can be formed on individuallytagged entities immediately after tagging. Alternatively, after mixingindividually tagged entities, either before or after the optionally useof library purification, or either before or after library enrichmentfor specific properties.

When tags and anti-tags are composed of nucleotides the complex consistsof a double stranded nucleotide, e.g. duplex DNA or hybrids DNA/RNA.

The purification chemical entity (denoted “@”) can be connected to theanti-tag. The purification chemical entity contains a recognizinggroup(s) such as e.g. nucleotide sequence(s), epitopes, reactive groups,high affine ligands a.o. The purification chemical entities can becomposed of monoclonal antibodies, bioactive species, proteins, DNA,RNA, LNA, PNA, natural bioactive species, unnatural bioactive species,polymeric or oligomeric hydrazine aryl or alkyl carboxylic acids,polymeric or oligomeric aminoxy aryl or alkyl carboxylic acids, othernatural polymers or oligomers, unnatural polymers (molecularweight >1000 Da) or oligomers (molecular weight <1000 Da), smallnon-polymeric molecules (molecular weight <1000 Da) or largenon-polymeric molecules (molecular weight >1000 Da). Purificationchemical entities may e.g. be a nucleotide sequence, biotin,streptavidin, avidin, “his-tags”, mercapto groups or disulfide/activateddisulfide groups. The purification chemical entity can be part of theanti-tag, e.g. in the case the anti-tag is nucleotide based or e.g.antibodies where part of the antibody may serve as epitop for anotherantibody (e.g. immobilized antibody which serve as purification filter).

Purification filters contains components which associate, interact orreact with purification chemical entities whereby a complex is formed.This complex allows separation of non-complexed tagged entities andcomplexed tagged entities. The purification filter contains arecognizing group(s) such as e.g. nucleotide sequence(s), epitopes,reactive groups, high affine ligands a.o. The purification filter can becomposed of monoclonal antibodies, bioactive species, proteins, DNA,RNA, LNA, PNA, natural bioactive species, unnatural bioactive species,polymeric or oligomeric hydrazino aryl or alkyl carboxylic acids,polymeric or oligomeric aminoxy aryl or alkyl carboxylic acids, othernatural polymers or oligomers, unnatural polymers (molecularweight >1000 Da) or oligomers (molecular weight <1000 Da), smallnon-polymeric molecules (molecular weight <1000 Da) or largenon-polymeric molecules (molecular weight >1000 Da). Purificationfilters may e.g. be a nucleotide sequence, biotin, strepdavidin, avidin,“his-tags”, mercapto groups or disulfide/activated disulfide groups.

The library is probed and enriched for properties. Properties can beaffinity, catalytic activity or membrane penetrating capability a.o.

Amplification may use PCR or RTPCR techniques. Anti-tags are amplifiablein some aspects of the invention. Anti-tags can be separated from tagsby use of physical or chemical means, such as e.g. UV-irradiation, heat,pH-adjustment, use of salt solutions a.o.

Isolated tagged entities can be identified either trough their tag oranti-tag. Identification can be accomplished by cloning of anti-tags andsequencing their DNA/RNA or through mass analysis of either taggedentities or anti-tags or complexes of anti-tags/tagged entities.

The library of tagged entities may involve 10-10²⁰ or 10-10¹⁴ or 10-10²or 10-10³ or 10²-10³ or 10²-10⁴ or 10³-10⁶ or 10³-10⁸ or 10³-10¹⁰ or10³-10¹⁴ or 10⁵-10⁶ or 10⁵-10⁸ or 10⁵-10¹⁰ or 10⁵-10¹⁴ or 10⁸-10¹⁴ or10¹⁴-10²⁰ entities.

Library complexes of tagged entities and anti-tags can be enriched forproperties prior to purification by use of purification chemical entityand purification filter or after purification.

The term unique, when used together with sequences of nucleotides,implies that at least one of the nucleobases and/or backbone entities ofthe sequence does not appear together with different chemical entities.Preferably, a specific sequence is unique due to fact that no otherchemical entities are associated with the same sequence of nucleobases.

Once the library has been formed, one must screen the library forchemical compounds having predetermined desirable characteristics.Predetermined desirable characteristics can include binding to a target,catalytically changing the target, chemically reacting with a target ina manner which alters/modifies the target or the functional activity ofthe target, and covalently attaching to the target as in a suicideinhibitor.

The target can be any compound of interest. The target can be a protein,peptide, carbohydrate, polysaccharide, glycoprotein, hormone, receptor,antigen, antibody, virus, substrate, metabolite, transition stateanalog, cofactor, inhibitor, drug, dye, nutrient, growth factor, cell,tissue, etc. without limitation. Particularly preferred targets include,but are not limited to, angiotensin converting enzyme, renin,cyclooxygenase, 5-lipoxygenase, IIL-10 converting enzyme, cytokinereceptors, PDGF receptor, type II inosine monophosphate dehydrogenase,β-lactamases, and fungal cytochrome P-450. Targets can include, but arenot limited to, bradykinin, neutrophil elastase, the HIV proteins,including tat, rev, gag, int, RT, nucleocapsid etc., VEGF, bFGF, TGFβ,KGF, PDGF, thrombin, theophylline, caffeine, substance P, IgE, sPLA2,red blood cells, glioblastomas, fibrin clots, PBMCs, hCG, lectins,selecting, cytokines, ICP4, complement proteins, etc.

The stringency conditions under which the library are screened arenormally limited to such condition that maintain the hybridisationbetween the identifier tag and the anti-tag. High stringency conditionscan be applied, however, followed by a renewed synthesis or attachmentof the anti-tag. Screening conditions are known to one of ordinary skillin the art.

Chemical compounds having predetermined desirable characteristics can bepartitioned away from the rest of the library while still attached to anucleic acid identifier tag by various methods known to one of ordinaryskill in the art. In one embodiment of the invention the desirableproducts are partitioned away from the entire library without chemicaldegradation of the attached nucleic acid such that the identifiernucleic acids are amplifiable. The identifier tag may then be amplified,either still attached to the desirable chemical compound or afterseparation from the desirable chemical compound.

In the most embodiment, the desirable chemical compound acts on thetarget without any interaction between the tag attached to the desirablechemical compound and the target. In one embodiment, the desirablechemical compounds bind to the target and the bound tag-desirablechemical compound-target complex can be partitioned from unboundproducts by a number of methods. The methods include nitrocellulosefilter binding, column chromatography, filtration, affinitychromatography, centrifugation, and other well known methods.

Briefly, the library is subjected to the partitioning step, which mayinclude contact between the library and a column onto which the targetis bound. All tags which have not formed hybridisation products with achemical entity-tag aggregate or those tags associated with undesirablechemical entities will pass through the column. Additional undesirablechemical entities (e.g., entities which cross-react with other targets)can be removed by counter-selection methods. Desirable complexes arebound to the column and can be eluted by changing the conditions of thecolumn (e.g., salt, etc.) or the tag associated with the desirablechemical compound can be cleaved off and eluted directly.

Additionally, chemical compounds which react with a target can beseparated from those products that do not react with the target. In oneexample, a chemical compound which covalently attaches to the target(such as a suicide inhibitor) can be washed under very stringentconditions. The resulting complex can then be treated with proteinase,DNAse or other suitable reagents to cleave a linker and liberate thenucleic acids which are associated with the desirable chemical compound.The liberated nucleic acids can be amplified.

In another example, the predetermined desirable characteristic of thedesirable product is the ability of the product to transfer a chemicalgroup (such as acyl transfer) to the target and thereby inactivate thetarget. One could have a product library where all of the products havea thioester chemical group. Upon contact with the target, the desirableproducts will transfer the chemical group to the target concomitantlychanging the desirable product from a thioester to a thiol. Therefore, apartitioning method which would identify products that are now thiols(rather than thioesters) will enable the selection of the desirableproducts and amplification of the nucleic acid associated therewith.

There are other partitioning and screening processes which arecompatible with this invention that are known to one of ordinary skillin the art. In one embodiment, the products can be fractionated by anumber of common methods and then each fraction is then assayed foractivity. The fractionization methods can include size, pH,hydrophobicity, etc.

Inherent in the present method is the selection of chemical entities onthe basis of a desired function; this can be extended to the selectionof small molecules with a desired function and specificity. Specificitycan be required during the selection process by first extractingidentifier sequences of chemical compounds which are capable ofinteracting with a non-desired “target” (negative selection, orcounter-selection), followed by positive selection with the desiredtarget. As an example, inhibitors of fungal cytochrome P-450 are knownto cross-react to some extent with mammalian cytochrome P-450 (resultingin serious side effects). Highly specific inhibitors of the fungalcytochrome could be selected from a library by first removing thoseproducts capable of interacting with the mammalian cytochrome, followedby retention of the remaining products which are capable of interactingwith the fungal cytochrome.

Following the selection procedure, anti-tags are recovered. The recoverycan be performed by subjecting the selected complexes to stringencyconditions which will detach the anti-tag sequences from the identifiertag. In the event the tag and the anti-tag are nucleic acids, thestringency conditions can be increased by increasing the temperaturegradually until the two strands of the double helix are melted apart.Further copies of anti-tag sequences can be provided by extension of theidentifier sequences using a suitable primer and a polymerase. In thealternative, the recovered anti-tag sequence and/or the identifiersequence tag can be subjected to PCR to form a double stranded product.The strands comprising the sequence that complements at least a part ofa unique identifier sequence are subsequently isolated.

The selected chemical entity can be attached to the target during theextension or amplification or can be detached from the target. In oneembodiment of the invention, it is preferred that the target isimmobilised and the chemical compound remain attached to the targetduring the extension or amplification, to allow for easy recovery of theextension or amplification product by simple elution. In another aspectthe selected chemical entities are separated from the unique identifiersequences, prior to, simultaneous with or subsequent to the recovery ofthe enrichment sequences.

In order to recover the desired anti-tag sequences, it can beappropriate to provide the native as well as the amplified, if present,anti-tag sequences with one part of a molecular affinity pair. The onepart of a molecular affinity pair is also referred to herein as achemical entity. The anti-tags may then be recovered by using the otherpart of the molecular affinity pair attached to a solid phase, which ispossible to isolate. The essential property of the molecular affinitypair is that the two parts are capable of interacting in order toassemble the molecular affinity pair. In the biotechnological field avariety of interacting molecular parts are known which can be used asthe molecular affinity pair. Examples include, but are not restricted toprotein-protein interactions, protein-polysaccharide interactions,RNA-protein interactions, DNA-DNA interactions, DNA-RNA interactions,RNA-RNA interactions, biotin-streptavidin interactions, enzyme-ligandinteractions, antibody-ligand interaction, protein-ligand interaction,etc.

A suitable molecular affinity pair is biotin-streptavidin. The anti-tagsequences can be provided with biotin, e.g. by using a primer attachedto a biotin moiety in the amplification or extension step and contactingthe biotin tagged anti-tag sequence with beads coated with streptavidin.

After the recovery of the anti-tag sequences, these are contacted withthe initial library or a fraction thereof and an enriched library isallowed to be formed by the hybridisation of the anti-tag sequences tothe cognate sequence of the unique identifier tag.

The method according to the invention can be repeated one or more times.In a second round of the method, the part of the single stranded librarynot recognized by an anti-tag sequence can be cleared from the reactionmedia or the remaining part of the single stranded library may remain inadmixture with the enrich library. In general, it is not necessary toseparate the remaining part of the single stranded library from themedia before the enriched double stranded library is subjected to asecond contact with the target because conditions for the preselectedfunction usually are more stringent than the first round, wherefore themembers of the single stranded library presumably will not bind to thetarget. However, to reduce the noise of the system, it can be useful atsome events to withdraw from the media the members of the singlestranded initial library not mated with an anti-tag sequence. If theanti-tag sequences are provided with one part of a molecular affinitypair, like biotin, the chemical compounds of interest can be extractedfrom the media by treatment with immobilized streptavidin, e.g beadscoated with streptavidin.

As mentioned above, the conditions for performing the second or furtherselection step is generally more stringent than in the first orpreceding step. The increasing stringency conditions in sequentialselection rounds provide for the formation of a sub-library of chemicalcompounds which is narrowed with respect to the number but enriched withrespect to the desired property.

In the present description with claims, the terms nucleic acid,oligonucleotide, oligo, and nucleotides are used frequently. The termsnucleotide, nucleotide monomer, or mononucleotides are used to denote acompound normally composed of two parts, namely a nucleobase moiety, anda backbone. The back bone may in some cases be subdivided into a sugarmoiety and an internucleoside linker. Mononucleotides can be linked toeach other to form a oligonucleotide. Usually, the mononucleotides arelinked through an internucleoside linkage. The term nucleic acid coversmononucleotides as well as oligonucleotides. Usually, however, the termdenotes an oligonucleotide having from 2 to 30 mononucleotides linkedtogether through internucleoside linkers.

Determining the Identifier Oligonucleotide of the Bifunctional Complex

The identifier oligonucleotide of the identifier sequence present in theisolated bifunctional molecules or the separated identifieroligonucleotides is determined to identify the chemical entities thatparticipated in the formation of the molecule. The synthesis method ofthe molecule can be established if information on the functionalentities as well as the point in time they have been incorporated in themolecule can be deduced from the identifier oligonucleotide. It can besufficient to get information on the chemical structure of the variouschemical entities that have participated in the molecule to deduce thefull molecule due to structural constraints during the formation. As anexample, the use of different kinds of attachment chemistries may ensurethat a chemical entity on a reactant can only be transferred to a singleposition on a scaffold. Another kind of chemical constrains can bepresent due to steric hindrance on the scaffold molecule or thefunctional entity to be transferred. In general however, it is preferredthat information can be inferred from the identifier sequence thatenable the identification of each of the chemical entities that haveparticipated in the formation of the molecule along with the point intime in the synthesis history the chemical entities have beenincorporated in the (nascent) molecule.

Although conventional DNA sequencing methods are readily available anduseful for this determination, the amount and quality of isolatedbifunctional molecule may require additional manipulations prior to asequencing reaction.

Where the amount is low, it is preferred to increase the amount of theidentifier sequence by polymerase chain reaction (PCR) using PCR primersdirected to primer binding sites present in the identifier sequence.

In addition, the quality of the isolated bifunctional molecule can besuch that multiple species of bifunctional molecules are co-isolated byvirtue of similar capacities for binding to the target. In cases wheremore than one species of bifunctional molecule are isolated, thedifferent isolated species must be separated prior to sequencing of theidentifier oligonucleotide.

Thus in one embodiment, the different identifier sequences of theisolated bifunctional complexes are cloned into separate sequencingvectors prior to determining their sequence by DNA sequencing methods.This is typically accomplished by amplifying all of the differentidentifier sequences by PCR as described herein, and then using a uniquerestriction endonuclease sites on the amplified product to directionallyclone the amplified fragments into sequencing vectors. The cloning andsequencing of the amplified fragments then is a routine procedure thatcan be carried out by any of a number of molecular biological methodsknown in the art.

Alternatively, the bifunctional complex or the PCR amplified identifiersequence can be analysed in a microarray. The array can be designed toanalyse the presence of a single tag or multiple tags in an identifiersequence.

EXAMPLES General Procedures

The following general procedures were used to synthesize libraries. Forexample one general procedure used is the reaction of a reactant with areactive site. Another general procedure used is the attachment of a tagto a nascent bifunctional complex. Yet another general procedure used isa purification of a nascent bifunctional complex or a quenching of areactive site, e.g. by reaction with a reactant such that the reactivesite was rendered unreactive. It is to be understood that any variablesuch as volume, amount, temperature, pressure, number, concentration,solvent type, reactant type, and composition described in the followinggeneral procedures can be varied according to specific needs. It is tobe understood that the results obtained by these general procedures canbe achieved with a vast number of other variant procedures.

General Procedures Containing a Volume Reduction Step:

V1) Volume Reduction by Lyophilization

The contents of wells were lyophilized in a speed vac

V2) Volume Reduction by Precipitation

The sample was precipitated using 0.1 volumes of 5 M NaCl and 0.5volumes of isopropanol or 1.5 volumes of ethanol and washed with cold70% ethanol. A sample of the material was analysed by polyacrylamide gelelectrophoresis and autoradiography to verify the efficiency ofdephosphorylation.

General Procedures Containing a Splitting Step:

S1) The total pool or a part of the pool the total pool was splitequally in 1-10.000 wells, e.g. 8, 16, 24, 32, 40, 48, 56, 64, 72, 80,88, 96, 192, 384, or 1536 wells.

General Procedures Containing a Mixing Step Include:

M1) The Contents of All Wells were Mixed to Form One Pool

M2) Different Pools were Formed by Mixing the Contents of DifferentWells

General Procedures Modifying a Reactant

B1) Method for Generating an Aliphatic Aldehyde

The material was redissolved in 25 μl NaIO4 (50 mM in Sodium AcetateBuffer pH 4 and shaken at 25° C. for 30 min. 25 μl 700 mM Phosphatebuffer pH 6.7 was added.

General Procedures Containing a Reaction of a Reactant with a ReactiveSite:

R1) Reactants Containing an Acid which Reacts with an Amine Forming anAmide Bond:

Bifunctional complexes were distributed to wells. Samples to undergoacylation were dissolved in 5 μl 200 mM Na-phosphate buffer pH 8.0 or100 mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0. Then, 4 μl specificreactant (100 mM in dimethylsulfoxide) was added to each well. Then 1 μlDMT-MM mix (0.36 M DMT-MM in water and 56 mM Na-phosphate buffer pH 8)was mixed in each well and the sample was incubate at 30° C. for 16hours.

R2) Reactants Containing an Isocyanate which can React with an AmineForming an Urea Bond:

Lyophilize the contents of all wells. Mix 2 ml 100 mM Na-Borate bufferpH 8, with 2 ml 100 mM Na-phosphate buffer, pH 8. Add 8 μl buffer mix toeach well. Add 1 μL specific BB in 300 mM CH3CN to each well. Mixcontents of each well. Incubate at 50 degrees celcius for 16 hours.

R3) Reactants Containing a Sulfonyl Group which can React with an AmineForming a Sulphonamide Bond:

Samples to undergo sulfonylation were dissolved in 8 μl 100 mM SodiumBorate buffer pH 9. 2 μl specific reactant (100 mM in tetrahydrofuran)was then to each well and incubated at 30° C. for 16 hours.

R4) Reactants Containing an Aldehyde Group which can React with aPrimary Amine Forming a Secondary Amine or with a Secondary AmineForming a Tertiary Amine:

Samples to undergo reductive amination were dissolved in 15 μl 200 mMNaOAc buffer pH 5.0 5 ul specific BB was added to each well (200 mM inDMSO) and incubate at 30° C. for 1 h. Then 5 μl of freshly prepared 140mM NaCNBH3 (REA000025; 8.8 mg/ml) in NaOAc buffer pH 5.0 to was addedeach well and the samples were incubated at 30° C. for 16 hours in aPCR-machine. Then 25 μl water was added to each sample.

R5) Reactants Containing a Halogenated Heteroaromatic Moiety which canReact with an Amine Forming a C—N Bond.

Samples to undergo nucleophilic aromatic substitution were dissolved in12 μl 100 mM Borate Buffer pH 9. Then 12 μl specific BB was added toeach well (100 mM in DMSO) and all wells were incubated for 16 hours at90° C. Then, 40 μl water was added to each sample.

R6) Reactants Containing an Amine which can React with an Acid Formingan Amide Bond.

The material was redissolved in 10 μl H2O. 15 μl 100 mM Sulfo-NHS inwater and 1 μl 100 mM EDC in water was added. The mixture was shaken at25° C. for 15 min. The material was purified in a spin columnequilibrated water directly into 1 μl 100 mM BB/RE in 100 mM sodiumphosphate buffer pH 8.0. The mixture was shaken for 45 min at 50° C. or16 hours at 37° C.

R7) Reactants Containing an Amine which can React with an Acid Formingan Amide Bond.

The material was redissolved in 35 μl 100 mM sodium phosphate buffer pH8.0. 10 μl 100 mM building block solution in water or DMSO was added.5.0 μl 500 mM DMT-MM in water was added. The mixture was incubated at30° C. for 2-24 hours.

R8) Reactants containing an aldehyde group which can react with aprimary amine forming a secondary amine or with a secondary amineforming a tertiary amine. The reaction being performed in organicsolvent (MeOH).

The material was applied to a DEAE (Diethyl aminoethyl) column which hadbeen washed 2 times with 10 mM Aq. AcOH. The material on DEAE was washedwith water followed by washing with MeOH. 10 μL 100 mM BB in DMSO and 40μL MeOH (dry) was added and the mixture was shaken at 600 rpm for 1 h at30° C. 10 μl NaCNBH₃ solution (140 mM in MeOH, freshly prepared) wasadded and the mixture was shaken overnight at 30° C. The material wasthen released from DEAE by adding 70 μl Release solution (1.5 M NaCl)and incubating at 25° C. for 10 minutes in an eppendorph thermoshaker at600 rpm. Water was added to the material to a final NaCl concentrationof 0.5 M. Then the material was precipitated by adding one volume ofisopropanol as described.

General Procedures Including Enabling or Including a Quality ControlStep:

QC1) Quality control of reactant reaction, e.g. reaction with anidentifier oligo Before a reactant reaction step, 10 μL of spike1 oligo[6TCAAGGAAGTAGGTCACGTA, where 6 is 6=5′C2OC2 aminomodifier, Glenresearch 10-1905] was added to specific wells. After a reactant reactionstep 2 μL sample was taken from specific wells and transferred to a96-well plate. 50 μL buffer which is compatible with mass spectrometryanalysis was added. A Mass spectrometry analysis was performed of thesample(s). The yield of a reaction of a reactant with a reactive sitewas thus evaluated.

QC2) Quality Control of Tag Addition

At some point during library synthesis tags labelled with a 5′phosphorus-32 was added to specific wells. Then, prior to performing atag addition step samples were taken from a number of wells. Thesesamples were pooled to serve as a marker before tag addition. Followinga tag addition, a 0.2 mm 10% PAGE gel was prepared and 0.5 μL sampleswere taken from a number of wells. PAGE loading buffer was added to thesamples. The samples were processed by PAGE including a molecular weightmarker suitably labelled. The gel was transferred to a support, wrappedin plastic, placed on film, exposed and developed. The efficiency of thetag addition (ligation) step was evaluated by comparing samples takenbefore and after tag addition.

QC3) Quality Control of Reactant Reaction

Before a reactant reaction step, 10 μL of spike1 oligo[6TCAAGGAAGTAGGTCACGTA, where 6 is 6=5′C2OC2 amino modifier, Glenresearch 10-1905] was added to specific wells. After a reactant reactionstep. Contents of selected wells were added to 50 μL prewashedstreptavidin sepharose. The spike1 oligo was captured by adding 500 pmolantispike1. (5TACGTGACCTACTTCCTTGA, where 5 is 5=5′ Biotin-c6-) andincubating for 5 minutes at 30 degrees celcius. The sample wascentrifuged for 1 minute. The flowthrough was removed and added back itto its well of origin. The streptavidin sepharose was washed 1× with 500μL 25 mM NH4Ac pH7.5 and 2 times with 500 μL dH2O. The spike 1 oligo waseluted from the streptavidin sepharose (elution repeated 2 times) with40 μL dH2O heated to 80 degrees celcius. The samples were purified e.g.using P6 [Biorad] and 10-20 μl was used for mass spectrometry analysesas described in general procedure QC2. The efficiency of reactantreactions could thus be determined.

QC4) Quality Control of a Step which Removes Tag or Renders themUnfunctional

Following the termination of a tag addition step, a specific tag(optionally with its anti-tag) was added. After library synthesis,library screening, tags were investigated for the presence of thespecific tag which would indicate that a purification following theaddition of that specific tag was not efficient.

General Procedures Containing a Purification Step: P1) Purification bySize-Exclusion Chromatography

1 mL of washed P6 slurry was added to the wells of a filter plate(Whatman Unifilter 96 well plates). The filter was placed on a 2 mLcollection plate and centrifuged for 4 minutes. The filterplate wasplaced on a collection plate (Eppendorff). The volume of samples to bepurified was adjusted to 20-70 μl. The SEC plate on top of thecollection plate was centrifuged 4 minutes at 900×RCF.

P2) Purification by Precipitation

The sample was precipitated using 0.1 volumes of 5 M NaCl and 0.5volumes of isopropanol or 1.5 volumes of ethanol and washed with cold70% ethanol. A sample of the material was analysed by polyacrylamide gelelectrophoresis and autoradiography to verify the efficiency ofdephosphorylation.

P3) PAGE Gel Purification

A 0.2, 1, or 2 mm thickness 6% or 10% acrylamide PAGE gel was prepared.A gel prerun was performed for 1 h at 60w. PAGE Loading buffer was addedto the material to be purified and denatured by incubation for 10 min. @80 C. The material was loaded on the gel and run for 1 h @ 60 w. The gelwas transferred to a plastic support, wrapped, placed on film, exosed,and developed. The gel was placed on the developed film. A gel slicecorresponding to the material of interest were cut from the gel bycomparing with the film. The exercised gel was distributed in aliquotsto filter columns. 500 μL 500 mM NH4Ac+1 mM EDTA pH 7.4 was added toeach tube, incubate on heated shaker @ 65° C. for 16 h. The material wasrecovered by centrifugation for 2 min @1000×RCF.

P4) Purification Using HPLC

Purification was done using a Reverse Phase HPLC with a Waters XterraRP8 column. A binary mobile phase gradient profile was used to elute theproduct using a 50 mM aqueous triethylammonium acetate buffer at pH 7.5and 99% acetonitrile/1% water solution. The purified material wasconcentrated by lyophilization and the resulting residue was dissolvedin 5 mL of water.

P5) Purification by Ion-Exchange Chromatography

The material was applied to a DEAE (Diethyl aminoethyl) column which hadbeen washed 2 times with 10 mM Aq. AcOH. The material on DEAE was washedextensively with water. The material was then released from DEAE byadding 200 μl Release solution (1.5 M NaCl) and incubating at 25° C. for10 minutes in an eppendorph thermoshaker at 600 rpm. Water was added tothe material to a final NaCl concentration of 0.5 M.

General Procedures Containing a Quenching Step:

Q1) Desphosphorylation to Remove 5′ Phosphates from Tags Rendering themUnable to Participate in a Tagging Step, e.g. a Ligation

The sample was dephosphorylated by first adding 80 μl SAP buffer (200 mMHepes pH 7.8, 100 mM MgCl₂) and 2 μl Shrimp Alkaline Phosphatase (USB,40 U/μl) to the sample followed by incubation of the sample at 37° C.for 1 hour. The phosphatase was inactivated by incubation at 68° C. for10 minutes. The sample was precipitated using 0.05 volumes of 5 M NaCland 50% isopropanol and washed with cold 70% ethanol. A sample of thematerial was analysed by polyacrylamide gel electrophoresis andautoradiography to verify the efficiency of dephosphorylation.

General Procedures Containing a Tagging Step:

T1) 10 μl buffer containing 120 mM HEPES(2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-ethanesulfonic acid) pH 7.8, 40mM MgCl₂, 40 mM DTT (dithiothretiol) and 4 mM ATP was added to eachwell. 500 μmol double-stranded tags (e.g., the combination A-0001 andAx-0001) was also added. Annealing was then performed by a 80° C. to 200ramp in a thermocycler (Eppendorf Mastercycler Gradient). 1 μl of T4 DNAligase (20 U/μl) was added to each well. Samples were then incubated ina PCR-machine with the following temperature profile: 25° C. for 10 min,45° C. for 10 min, and 25° C. for 10 min. The ligase was inactivated byincubating samples at 68° C. for 10 min.

General Procedures Containing a Deprotection Step: D1) Remove FmocProtection Groups on a DEAE Ion Exchange Column Releasing an Amine

This procedure can also be used for removal of msec protection groups

Fmoc (fluorenylmethoxycarbonyl) Protection Group:

To remove the Fmoc protection group, the material was applied to a DEAE(Diethyl aminoethyl) column which had been washed 2 times with 10 mM Aq.AcOH. The material on DEAE was washed with water and 2 mL 10% Piperidinein dH2O was added folling by incubation for 10 min at RT. A further 2 mL10% Piperidine in dH2O was added and incubated for 10 min @ RT. Thecolumn was drained and washed with 4×10 ml dH2O. The material was elutedby adding 750 μL Release Solution (1.5M NaCl). Incubate @ 60 C onshaker. Optionally repeat elution/release step.

D2) Remove Ns Protection Groups in Organic Solvent on a DEAE IonExchange Column Ns (2-Nitro-benzenesulfonyl) Protection Group:

To remove the Ns protection group, the material was applied to a DEAE(Diethyl aminoethyl) column which had been washed 2 times with 10 mM Aq.AcOH. The material on DEAE was washed with water followed by washingwith DMF (dimethyl formamide). Then the material on DEAE was incubatedin a solution of 0.5M mercaptoethanol and 0.25 M DIPEA(N,N′-Diisopropylethylamine) in dimethyl formamide and incubated for 24hours at 25° C. in an eppendorph thermoshaker at 600 rpm. Then thematerial on DEAE was washed with 0.3M AcOH in DMF, then twice with DMFand then with water. The Ns-deprotected material was then released fromDEAE by adding 70 μl Release solution (1.5 M NaCl) and incubating at 25°C. for 10 minutes in an eppendorph thermoshaker at 600 rpm. Water wasadded to the material to a final NaCl concentration of 0.5 M. Then thematerial was precipitated by adding one volume of isopropanol asdescribed.

D3) Remove Fmoc Protection Groups in Aqueous Solution

This procedure can also be used for removal of msec protection groups inaqueous solution

Samples were redissolved in water and adjusted to 6% piperidine. Sampleswere then incubated at 25° C. for 30 minutes to remove Fmoc protectiongroups.

D4) Remove Msec Protection Groups in Aqueous Solution

Msec (2-(methyl sulfonyl)ethyl carbamate) protection group used forprotection of primary amines:

Msec protection groups were removed by dissolving the material in 25 μl0.1 M Sodium Borate Buffer pH 10 and incubating at 40° C. for 3 hours.Then the material was lyophilized and dissolved in 85 μl H₂O.

D5) Remove tBu, Me, and Et Protection Groups Releasing the CarboxylicAcid in Aqueous Solution

The lyophilized material was dissolved in 20 μL 100 mM LiOH andincubated at 80° C. in PCR machine for 30 minutes. 40 μL 100 mM NaOAcbuffer pH 5 was added tBu protection group:

D6) Remove Boc Protection Group Releasing the Amine in Aqueous Solution

The lyophilized material was dissolved in 20 μL 37.5 mM NaOAc and 5 μL1M MgCl2 and incubated at 70° C. ON (Lid 100° C.) in PCR-machine

Boc Protection Group:

D6) Remove TFAc Protection Group Releasing the Amine in Aqueous Solution

The lyophilized material was dissolved in 20 μl and incubated at 45° C.ON (Lid 50° C.) in PCR-machine for 18 hours.

TFAc Protection Group:

Example 1 Synthesis and Affinity Selection of a Library Encoding on theOrder of 65.000 Scaffolded Compounds

This example illustrates the use of general procedures in the followingorder:

Position A building blocks (reactants) and tags: R1-P1-T1-P1-Q1-V2,Position B building blocks (reactants) and tags: T1-P1-R1-P1-Q1-D4-V1,Position C building blocks (reactants) and tags:T1-P1-(R1/R3/R2)-P1-Q1-V2-D2-V2,Position D building blocks (reactants) and tags:T1-P1-(R1/R2/R3/R4/R5)-P1-D3-V2-P3

A library on the order of 65.000 DNA-tagged small molecules wassynthesized. The synthesized small molecules were scaffolded (branched).

Scheme 1.1. Layout of the synthesized display molecules. R₃X₃ buildingblocks (reactants) included sulfonyl chlorides (Ar₃—SO₂—Cl), acids(R₃—COOH), and isocyanates (R₃—N═C═O). R₄X₄ building blocks (reactants)included chloro- and fluoro-substituted heteroaromates (HetAr—Cl/F),aldehydes (R₄—C═O), acids (R₄—COOH), sulfonyl chlorides (Ar₃—SO₂—Cl),and isocyanates (R₃—N═C═O)

The first set of building blocks (reactants) (see table 1.5A) wereloaded onto a display oligo:

Subsequently, Fmoc protection groups present on the loaded buildingblocks (reactants) was removed by incubating them in a solution of 6%piperidine in water at 25° C. for 30 minutes. Samples were then purifiedusing P-6 gel filtration spin columns (Biorad).

900 μmol Display oligo was added to each of 16 wells. In each well thedisplay oligo carried a specific building block (position A buildingblock).

Ligation of A-Tags

10 μl buffer containing 120 mM HEPES(2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-ethanesulfonic acid) pH 7.8, 40mM MgCl₂, 40 mM DTT (dithiothretiol) and 4 mM ATP was added to eachwell. 500 μmol double-stranded A-codons (e.g., the combination A-0001and Ax-0001) was also added (See table 1.4A for tags and correspondingbuilding blocks (reactants)). Annealing was then performed by a 80° C.to 200 ramp in a thermocycler (Eppendorf Mastercycler Gradient) In onewell 50 μmol double-stranded 5′ phosphate 32-labeled A-codon was added.1 μl of T4 DNA ligase (20 U/μl) was added to each well. Samples werethen incubated in a PCR-machine with the following temperature profile:25° C. for 10 min, 45° C. for 10 min, and 25° C. for 10 min. The ligasewas inactivated by incubating samples at 68° C. for 10 min. 25 ul ofwater was then added to each sample. To allow verification of theefficiency of the following dephosphorylation step, a “Dummy A” codonlabelled with 5′ phosphorus-32 was added to a sample. Bifunctionalcomplexes were purified using gel-filtration with Bio-Gel P-6, (Bio-Rad)and the contents of the wells were pooled.

Desphosphorylation

The pooled sample was dephosphorylated by first adding 80 μl SAP buffer(200 mM Hepes pH 7.8, 100 mM MgCl2) and 2 μl Shrimp Alkaline Phosphatase(USB, 40 U/μl) to the pooled sample followed by incubation of the sampleat 37° C. for 1 hour. The phosphatase was inactivated by incubation at68° C. for 10 minutes. The sample was precipitated using 0.05 volumes of5 M NaCl and 50% isopropanol and washed with cold 70% ethanol. A sampleof the material was analysed by polyacrylamide gel electrophoresis andautoradiography to verify the efficiency of dephosphorylation.

Ligation of B-Tags

The sample was dissolved in water and distributed equally to 16 wells.To each well 750 μmol double-stranded B-codon was added and ligation anddephosphorylation was performed as described for the ligation ofA-codons. After ligation and inactivation of the enzyme, the sampleswere lyophilized.

Load of Position B Building Blocks (Reactants)

Each sample was dissolved 5 μl 200 mM Na-phosphate buffer pH 8.0 or 100mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0 according to previouslyidentified reaction conditions. To each well was added add 4 μl solutionof a building block (100 mM in dimethyl sulfoxide). For each well 0.72μl 0.5M DMT-MM solution in water was mixed with 0.28 μl 200 mMNa-phosphate buffer pH 8 and added to the well. The wells were thenincubated at 30° C. for 16 hours in a PCR-machine (EppendorfMastercycler Gradient). Then, 40 μl of water was added to each sample.Samples were purified using gel-filtration with Bio-Gel P-6, (Bio-Rad).The samples were pooled and purified by isopropanol precipitation asdescribed.

Desphosphorylation

The pooled sample was dephosphorylated by first adding 80 μl buffercontaining 200 mM HEPES pH 7.8 and 100 mM MgCl₂ and 2 μl Shrimp AlkalinePhosphatase (USB, 40 U/μl) to the pooled sample followed by incubationof the sample at 37° C. for 1 hour. The phosphatase was inactivated byincubation at 68° C. for 10 minutes. The sample was precipitated using0.05 volumes of 5 M NaCl and 50% isopropanol and washed with cold 70%ethanol. A sample of the material was analysed by polyacrylamide gelelectrophoresis and autoradiography to verify the efficiency ofdephosphorylation.

Msec Deprotection

Primary amines of position B building blocks (reactants) were protectedby Msec groups:

Msec protection groups were removed by dissolving the material in 25 μl0.1 M Sodium Borate Buffer pH 10 and incubating at 40° C. for 3 hours.Then the material was lyophilized and dissolved in 85 μl H₂O.

Ligation of C-Tags

In each well ligation of double-stranded C-codons were performed asdescribed for A- and B-codons.

Load of Position C Building Blocks (Reactants)

Samples to undergo isocyanate addition were redissolved in 8 μl buffer(100 mM sodium borate and 100 mM sodium phosphate pH 8.0). 1 μl of aspecific building block (300 mM in CH₃CN) was added to each well andincubated at 50° C. for 16 hours. Then, 40 μL of water was added to eachsample.

Samples to undergo sulfonylation were dissolved in 8 μl 100 mM SodiumBorate buffer pH 9. Then 2 μl specific building block (100 mM intetrahydrofuran) was then to each well and incubated at 30° C. for 16hours. Then, 40 μl of water was added to each sample.

Samples to undergo acylation were dissolved in 5 μl 200 mM Na-phosphatebuffer pH 8.0 or 100 mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0.Then, 4 μl specific building block (100 mM in dimethylsulfoxide) wasadded to each well. Then 1 μl DMT-MM mix (0.36 M DMT-MM in water and 56mM Na-phosphate buffer pH 8) was mixed in each well and the sample wasincubate at 30° C. for 16 hours. Then, 40 μl water was added to eachsample.

Samples were purified by gel-filtration as described.

Desphosphorylation

The pooled sample was dephosphorylated by first adding 80 μl buffer (200mM Hepes pH 7.8, 100 mM MgCl2) and 2 μl Shrimp Alkaline Phosphatase(USB, 40 U/μl) to the pooled sample followed by incubation of the sampleat 37° C. for 1 hour. The phosphatase was inactivated by incubation at68° C. for 10 minutes. The sample was precipitated using 0.05 volumes of5 M NaCl and 50% isopropanol and washed with cold 70% ethanol. A sampleof the material was analysed by polyacrylamide gel electrophoresis andautoradiography to verify the efficiency of dephosphorylation.

Ns Protection Group Removal

Secondary amines of position B building blocks (reactants) wereprotected using Ns:

To remove the Ns protection group, the material was applied to a DEAE(Diethyl aminoethyl) column which had been washed 2 times with 10 mM Aq.AcOH. The material on DEAE was washed with water followed by washingwith DMF (dimethyl formamide). Then the material on DEAE was incubatedin a solution of 0.5M mercaptoethanol and 0.25 M DIPEA(N,N′-Diisopropylethylamine) in dimethyl formamide and incubated for 24hours at 25° C. in an eppendorph thermoshaker at 600 rpm. Then thematerial on DEAE was washed with 0.3M AcOH in DMF, then twice with DMFand then with water. The Ns-deprotected material was then released fromDEAE by adding 70 μl Release solution (1.5 M NaCl) and incubating at 25°C. for 10 minutes in an eppendorph thermoshaker at 600 rpm. Water wasadded to the material to a final NaCl concentration of 0.5 M. Then thematerial was precipitated by adding one volume of isopropanol asdescribed.

Ligation of D-Tags

D-tags were ligated as described. Then samples were purified usinggel-filtration as described and lyophilized.

Load of Position D Building Blocks (Reactants)

Samples to undergo isocyanate addition were redissolved in 8 μl buffer(100 mM sodium borate and 100 mM sodium phosphate pH 8.0) 1 μl of aspecific building block (300 mM in CH₃CN) was added to each well andincubated at 50° C. for 16 hours. Then, 40 μL of water was added to eachsample.

Samples to undergo sulfonylation were dissolved in 8 μl 100 mM SodiumBorate buffer pH 9. 2 μl specific building block (100 mM intetrahydrofuran) was then to each well and incubated at 30° C. for 16hours. Then, 40 μl of water was added to each sample.

Samples to undergo acylation were dissolved in 5 μl 200 mM Na-phosphatebuffer pH 8.0 or 100 mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0.Then, 4 μl specific building block (100 mM in dimethylsulfoxide) wasadded to each well. Then 1 μl DMT-MM mix (0.36 M DMT-MM in water and 56mM Na-phosphate buffer pH 8) was mixed in each well and the sample wasincubate at 30° C. for 16 hours. Then, 40 μl water was added to eachsample.

Samples to undergo reductive amination were dissolved in 15 μl 200 mMNaOAc buffer pH 5.0 5 ul specific BB was added to each well (200 mM inDMSO) and incubate at 30° C. for 1 h. Then 5 μl of freshly prepared 140mM NaCNBH3 (REA000025; 8.8 mg/ml) in NaOAc buffer pH 5.0 to was addedeach well and the samples were incubated at 30° C. for 16 hours in aPCR-machine. Then 25 μl water was added to each sample.

Samples to undergo nucleophilic aromatic substitution were dissolved in12 μl 100 mM Borate Buffer pH 9. Then 12 μl specific BB was added toeach well (100 mM in DMSO) and all wells were incubated for 16 hours at90° C. Then, 40 μl water was added to each sample.

Samples were then purified by gel-filtration as described.

Fmoc Deprotection

Samples were redissolved in water and adjusted to 6% piperidine. Sampleswere then incubated at 25° C. for 30 minutes to remove Fmoc protectiongroups. Samples were then again precipitated using isopropanol.

The combined material was redissolved in water and adjusted withpolyacrylamide gel electrophoresis loading buffer. The material waselectrophoresed and purified by isolating the material corresponding tobifunctional complexes with 4 tags. The single stranded bifunctionalcomplexes were eluted from the gel, precipitated using isopropanol asdescribed, and purified by gel-filtration as described.

Affinity Selection

Prior to selection the single stranded bifunctional complexes wereconverted to double-stranded for by extending a primer containing asequence informative of the selection using the single-stranded tag ofthe bifunctional comples as a template. 200 μmol primer(5′-AAGGAACATCATCATGGAT) was mixed with 20 μmol bifunctional complexesand lyophilized. The sample was redissolved in 2.5 reaction buffer and 5μl each dNTP (25 mM stock concentration) was added. The mixture washeated to 80° C. and slowly cooled to 55° C. Then 2.5 μl Taq Polymerase(5 units/μl) was added and the extension reaction was allowed to proceedfor 1 hour. Then 25 μl water was added and the sample was purified usinggel-filtration and used for affinity selection.

A fraction of the obtained bifunctional complexes was lyophilized anddissolved in 5 μl thrombin buffer (137 mM NaCl, 2.7 mM KCl, 10 mM sodiumphosphate, 0.1% PEG8000). 50 μl streptavidin sepharose (AmershamBiosciences) slurry was washed in 4×100 μl thrombin buffer andresuspended in 50 μl thrombin buffer. Then 2 units biotinylated thrombin(Novagen) was added to the streptavidin sepharose slurry and the slurrywas incubated at 15° C. with agitation (1400 rpm) for 30 minutes andsubsequently washed 4 times with 100 μl thrombin buffer. A 10 μlEppendorf tip was packed with glass wool up to the 2.5 μl mark. Thestreptavidin sepharose was applied to the tip and washed 3 times with100 μl thrombin buffer by applying vacuum to the bottom end of the tip.The library was applied to the column and allowed to soak in. Then thecolumn was washed 5 times with 100 μl thrombin buffer. Bifunctionalcomplexes were eluted by applying 25 μl of a nanomolar ligand (100 μM inPBS) to the column for 10 min followed by centrifugation of the column(1000 rcf for 30 seconds). An additional 25 μl PBS was applied to thecolumn and spun through. The eluted material was re-applied to a freshcolumn. This cycle was repeated 4 times. A 10 μl sample of elutedmaterial was used PCR using the forward and reverse primers5′-CAAGTCACCAAGAATTCATG and 5′-AAGGAACATCATCATGGAT. The PCR product wascloned and sequenced using standard methods.

TABLE 1.1 Layout of tags (A, B, C, and D) and anti-tags (Ax, Bx, Cx, Dx)showing codons (XXXXXXXXXXXXXXXXXXXX). The specific nucleotide sequencesof overhang sequences are shown. A XXXXXXXXXXXXXXXXXXXXCCTAGGACCA BXXXXXXXXXXXXXXXXXXXXGTGTCACTTA C XXXXXXXXXXXXXXXXXXXXGTGCACGTGT DXXXXXXXXXXXXXXXXXXXXGAATTCTACTCTCCTCAAGGTGATCCA TGATGATGTTCCTT AxXXXXXXXXXXXXXXXXXXXXCATGAATTCTTGGTGACTTG BxXXXXXXXXXXXXXXXXXXXXTGGTCCTAGG Cx XXXXXXXXXXXXXXXXXXXXTAAGTGACAC DxXXXXXXXXXXXXXXXXXXXXACACGTGCAC

TABLE 1.2 Examples of specific tags and antitags. Both codon andoverhang sequences are shown. Tag Sequence A-0001pTGTTGTCCATGATGCTTCCTCCTAGGACCA A-0002 pCAACTTGATCTCCAGTCGTCCCTAGGACCAB-0001 pCTAGTGGTCGAAGTTGCACAGTGTCACTTA B-0002pCCTACGTCTTCATGGACCTTGTGTCACTTA C-0001 pTTCGTCCATGCACATGATCTGTGCACGTGTC-0002 pCAGTTCCTCCAAGCAGTAGGGTGCACGTGT D0001pGTTCATCGTCTTCTAGGTGCGAATTCTACTCTCCTCAAGGT GATCCATGATGATGTTCCTT D0002pTGAGGTTCGAGGTTGACGATGAATTCTACTCTCCTCAAGGT GATCCATGATGATGTTCCTT Ax-0001AGGAAGCATCATGGACAACACATGAATTCTTGGTGACTTG Ax-0002GACGACTGGAGATCAAGTTGCATGAATTCTTGGTGACTTG Bx-0001TGTGCAACTTCGACCACTAGTGGTCCTAGG Bx-0002 AAGGTCCATGAAGACGTAGGTGGTCCTAGGCx-0001 AGATCATGTGCATGGACGAATAAGTGACAC Cx-0002CCTACTGCTTGGAGGAACTGTAAGTGACAC Dx-0001 GCACCTAGAAGACGATGAACACACGTGCACDx-0002 ATCGTCAACCTCGAACCTCAACACGTGCAC “p” denotes a 5′ phosphate

TABLE 1.4A Building blocks (reactants) used in synthesis position A andcodons of the corresponding A-tags BB A Tag A codon BlankAGTGCTCACACGACTGCTCG BBA000008 AGCTACGACAAGACTAGGAT BBA000890CGTCCACTACCATCGACGAC BBA001092 CCAACTTGTAGGTGAGGACT REA000251CTGCTGTTGGACTGCTTGTA REA000252 CTTCCAGGTCCTCGTAGTTC REA000778AACATGCTCTAGGTGTCGTC REA001185 ACCTGCACCTGGATGGATCG REA001315AACGAGGTCAGACGAAGCAC REA001763 CTCTCTAGTCCACAAGATGC REA001764ATCTCAAGTACGACACATCC REA001766 CCATCACATCAGCAGGTAGA REA001774TGTGTTGTGCTTGACCATCC REA001775 CAGACCTGTCTCCACGTAGC REA001776GCACTTGTCGATCAAGCAGA REA001779 TGGTCCTTGCTTGATGGAGT Dummy AATCGTACAGACTCCTCACAG

TABLE 1.4 Building blocks (reactants) used in synthesis position B andcodons of the corresponding B-tags BB B Tag B codon BlankTCCAAGCACGTCTCGTACTC REA001706 GGTCGACCAGATGGACACTT REA001710CATCATCTGTACAGGATGGT REA001711 TTCCAACTGCAAGGTACAGG REA001713TAGCACCTACAAGATGGAGT REA001714 CTCGACACCAGGTCCAGAAG REA001720GGTCATCTGAGCAACGTTGT REA001732 CACAAGCTAGGTACATGGAC REA001737TGCAGCAGCTTGCTCGTACT REA001738 GTCCATGTCCAAGCATGAAG REA001739TCCATCTCTAGGTTGCACAC REA001740 ATGCTACACCACTGCTGTGC REA001741CAACATGGAGAGTGGAACAT REA001742 ACTCCATCCACTTCACAGAG REA001743CTCCAGACTACCTGTGGACG REA001744 CGAGCAAGACATGAGCACTC Dummy BCCTCGTCCTGATGTTGCATC

TABLE 1.4C Building blocks (reactants) used in synthesis position C andcodons of the corresponding C-tags BB C Tag C codon BlankTCAGAACCATGCACTTGACG REA001526 GGAACATGCTGGAAGACCAG REA001527TACAGACTGAGCTTCACTTG REA001534 TCCTGATGGTGTACCACCTT REA001535AAGCAGCTCTGTCGAGCAAT REA001537 ATCAACCAAGGACATCTCTG REA000032CCTTGTAGGTCGTAGTGCAT REA001467 ACCTTCACGATCAGAGCTAT REA001469GATGTTGAGGACGTAGTGTG REA001471 CTTCGTCGAAGACTGAGTCA REA001475ACGACTGTCGTACGAGACGT BBA000820 CGATCTGGTTGACGAACAGC BBA000828CCACGATCTTGAGTGTACGG BBA000836 CACTGAGCAGCTTCTTCCAT REA000736CTCTTGGTTCCTAGGAGACA REA001712 GTCAGGACAACTCAGTGCAG Dummy CCGTGCTACCACACTCACAAT

TABLE 1.4D Building blocks (reactants) used in synthesis position D andcodons of the corresponding D-tags BB D Tag D codon BlankTCACATGACCAGCACGTGCG REA001526 CGATCAAGCTACAGAAGAAG REA001527TGGACTCTGTCGAAGGTACA REA001535 CTGTAGCATCCACTCCATCC REA000032GACTGTGGTGACACCTGACT REA001467 GCTTCGACAGACATCACTCG REA001469ATGGACAGTGGACACTCATT BBA000031 GCTTCTCCTGGTTGATGGTC REA000736CGTCGATGGACGTGTCGATT REA002313 CGTTCCAACCAACCTTGGAG REA000457CGAACAGAACTAGCACGTCA REA001223 GAAGTTCCTCTGGTCTAGGG REA001366GGTCTAGTAGCATGATCGAA REA001263 CTTCTTGGAACCTGAGCTTA REA001516TTGCTCAGCATCCTTGAACT REA001754 TGTTCCTGGTACACGAGGAG

TABLE 1.5A Position A building blocks (reactants). The unprotectedstructures are shown. The primary amines were protected by Fmoc groupsduring loading. After loading the Fmoc groups were removed.

TABLE 1.5B Position B building blocks (reactants). The unprotectedstructures are shown. The primary amines were protected by Msec groupsand secondary amines were protected by Ns during loading. After loadingthe protection groups were removed sequentially.

TABLE 1.5C Position C building blocks (reactants).

TABLE 1.5D Position D building blocks (reactants).

Selection Results

TABLE 1.6 Selection output sample showing the number of observations (n)of each combination of codons A, B, C, and D. Position n A B C D 2BBA001092 REA001710 BBA000820 BBA000031 3 REA001764 REA001710 REA001526BBA000031 1 REA001315 REA001710 REA001537 BBA000031 6 BBA000890REA001710 REA001712 BBA000031 4 REA001774 REA001710 REA001712 BBA0000313 REA000252 REA001710 REA001712 BBA000031 2 REA000251 REA001710REA001712 BBA000031 1 REA001775 REA001710 REA001712 BBA000031 1REA001764 REA001710 REA001712 BBA000031 2 BBA000890 REA001710 REA001712REA001535 4 REA001185 REA001720 REA001471 BBA000031 3 REA001766REA001732 REA001526 REA001535 1 REA001766 REA001732 REA001527 REA0015271 REA001766 REA001732 REA001527 REA001535

The building block combination X-REA001710-REA001712-BBA000031 (X can bedifferent position A building blocks (reactants)) corresponds to ligandswith Ki values against human thrombin in the low nanomolar tosubnanomolar range (Tucker T J et al. J. Med. Chem. 1998, 41,3210-3219):

Example 2 Synthesis and Affinity Selection of a Library Encoding on theOrder of 85.000.000 Compounds

A library encoding approximately 85.000.000 compounds was generatedusing 4 rounds of building block addition.

The first set of building blocks (reactants) were loaded onto a displayoligo:

Display Oligo

Subsequently, Fmoc protection groups present on the loaded buildingblocks (reactants) was removed by incubating them in a solution of 6%piperidine in water at 25° C. for 30 minutes. Samples were then purifiedusing P-6 gel filtration spin columns (Biorad).

900 μmol Display oligo was added to each of 96 wells. In each well thedisplay oligo carried a specific building block (position A buildingblock).

Ligation of A-Tags

10 ul buffer (120 mM Hepes pH 7.8, 40 mM MgCl2, 40 mM DTT and 4 mM ATP)was added to each well. 500 μmol double-stranded A-codons (e.g., thecombination A-0001 and Ax-0001) was also added. Annealing was thenperformed by a 80° C. to 20° ramp in a PCR machine (EppendorfMastercycler Gradient) In one well 50 μmol double-stranded 5′ phosphate32-labeled A-codon was added. 1 μl of T4 DNA ligase (20 U/μl) was addedto each well. Samples were then incubated in a PCR-machine with thefollowing temperature profile: 25° C. for 10 min, 45° C. for 10 min, and25° C. for 10 min. The ligase was inactivated by incubating samples at68° C. for 10 min. 25 ul of water was then added to each sample. Toallow verification of the efficiency of the following dephosphorylationstep, a “Dummy A” codon labelled with 5′ phosphor-32 was added to asample. Bifunctional complexes were purified using gel-filtration withBio-Gel P-6, (Bio-Rad) and pooled.

Desphosphorylation

The pooled sample was dephosphorylated by first adding 92 μl SAP buffer(200 mM Hepes pH 7.8, 100 mM MgCl2) and 4 μl Shrimp Alkaline Phosphatase(USB, 40 U/μl) to the pooled sample followed by incubation of the sampleat 37° C. for 1 hour. The phosphatase was inactivated by incubation at68° C. for 10 minutes. The sample was precipitated using 0.05 volumes of5 M NaCl and 50% isopropanol and washed with cold 70% ethanol. A sampleof the material was analysed by polyacrylamide gel electrophoresis andautoradiography to verify the efficiency of dephosphorylation.

Ligation of B-Tags

The sample was dissolved in water and distributed equally to 96 wells.To each well 750 μmol double-stranded B-codon was added and ligation anddephosphorylation was performed as described for the ligation ofA-codons. After ligation and inactivation of the enzyme, the sampleswere lyophilized.

Load of Position B Building Blocks (Reactants)

Each sample was dissolved 5 μl 200 mM Na-phosphate buffer pH 8.0 or 100mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0 according to previouslyidentified reaction conditions. To each well was added add 4 μl solutionof a building block (100 mM in dimethyl sulfoxide). For each well 0.72μl 0.5M DMT-MM solution in water was mixed with 0.28 μl 200 mMNa-phosphate buffer pH 8 and added to the well. The wells were thenincubated at 30° C. for 16 hours in a PCR-machine (EppendorfMastercycler Gradient). Then, 40 μl of water was added to each sample.Samples were purified using gel-filtration with Bio-Gel P-6, (Bio-Rad).The samples were pooled and purified by isopropanol precipitation asdescribed.

Fmoc Deprotection

Samples were redissolved in water and adjusted to 6% piperidine. Sampleswere then incubated at 25° C. for 30 minutes to remove Fmoc protectiongroups. Samples were then again precipitated using isopropanol. Thesamples were redissolved in water and distributed equally to 96 wells.

Ligation of C-Tags

In each well ligation of double-stranded C-codons were performed asdescribed for A- and B-codons.

Load of Position C Building Blocks (Reactants)

Position C building blocks (reactants) were loaded as described forposition B building blocks (reactants). Following loading, the sampleswere gel-filtration purified, desphosphorylated, precipitated usingisopropanol and Fmoc protection groups were removed as described.

Ligation of D-Tags

D-codons were ligated as described. Then samples were purified usinggel-filtration as described and lyophilized.

Load of Position D Building Blocks (Reactants)

Samples to undergo isocyanate addition were redissolved in 8 μl buffer(100 mM sodium borate and 100 mM sodium phosphate pH 8.0) 1 μl of aspecific building block (300 mM in CH₃CN) was added to each well andincubated at 50° C. for 16 hours in a in PCR-machine (EppendorfMastercycler Gradient). Then, 40 μL of water was added to each sample.

Samples to undergo sulfonylation were dissolved in 8 μl 100 mM SodiumBorate buffer pH 9. 2 μl specific building block (100 mM intetrahydrofuran) was then to each well and incubated at 30° C. for 16hours in a PCR-machine. Then, 40 μl of water was added to each sample.

Samples to undergo acylation were dissolved in 5 μl 200 mM Na-phosphatebuffer pH 8.0 or 100 mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0.Then, 4 μl specific building block (100 mM in dimethylsulfoxide) wasadded to each well. Then 1 μl DMT-MM mix (0.36 M DMT-MM in water and 56mM Na-phosphate buffer pH 8) was mixed in each well and the sample wasincubate at 30° C. for 16 hours in a PCR-machine. Then, 40 μl water wasadded to each sample.

Samples were purified by gel-filtration as described.

Fmoc Deprotection

Samples were redissolved in water and adjusted to 6% piperidine. Sampleswere then incubated at 25° C. for 30 minutes to remove Fmoc protectiongroups. Samples were then again precipitated using isopropanol.

The combined material was redissolved in water and adjusted withpolyacrylamide gel electrophoresis loading buffer. The material waselectrophoresed and purified by isolating the material corresponding tobifunctional complexes with 4 tags. The single stranded bifunctionalcomplexes were eluted from the gel, precipitated using isopropanol asdescribed, and purified by gel-filtration as described.

Prior to selection the single stranded bifunctional complexes wereconverted to double-stranded for by extending a primer containing asequence informative of the selection using the single-stranded tag ofthe bifunctional complexes as a template. 200 μmol primer(5′-TCTGGTGGTCTACGTGCTCTAAGGAACATCATCATGGATC) was mixed with 20 μmolbifunctional complexes and lyophilized. The sample was redissolved in2.5 reaction buffer and 5 μl each dNTP (25 mM stock concentration) wasadded. The mixture was heated to 80° C. and slowly cooled to 55° C. Then2.5 μl Taq Polymerase (5 units/μl) was added and the extension reactionwas allowed to proceed for 1 hour. Then 25 μl of water was added and thesample was purified using gel-filtration and used for affinityselection.

Selection

A fraction of the obtained bifunctional complexes was lyophilized anddissolved in 5 μl thrombin buffer (137 mM NaCl, 2.7 mM KCl, 10 mM sodiumphosphate, 0.1% PEG8000). 50 μl streptavidin sepharose (AmershamBiosciences) slurry was washed in 4×100 μl thrombin buffer andresuspended in 50 μl thrombin buffer. Then biotinylated thrombin(Novagen—2 units) was added to the streptavidin sepharose slurry and theslurry was incubated at 15° C. with agitation (1400 rpm) for 30 minutesand subsequently washed 4 times with 100 μl thrombin buffer. A 10 μlEppendorf tip was packed with glass wool up to the 2.5 μl mark. Thestreptavidin sepharose was applied to the tip and washed 3 times with100 μl thrombin buffer by applying vacuum to the bottom end of the tip.The library was applied to the column and allowed to soak in. Then thecolumn was washed 5 times with 100 μl thrombin buffer. Bifunctionalcomplexes were eluted by applying 25 μl of a nanomolar ligand (100 μM inPBS) to the column for 10 min followed by centrifugation of the column(1000 rcf for 30 seconds). An additional 25 μl PBS was applied to thecolumn and spun through. The eluted material was re-applied to a freshcolumn. This cycle was repeated 4 times. A 10 μl sample of elutedmaterial was used PCR using the forward and reverse primers5′-CAAGTCACCAAGAATTCATG and 5′-TCTGGTGGTCTACGTGCTCT. The PCR product wasclones and sequenced using standard methods.

Selection Results

TABLE 2.1 Selection output sample showing the number of observations (n)of each combination of codons A, B, C, and D. Position n A B C D 1REA002420 REA001464 REA001829 REA002088 1 REA001821 REA001710 BBA001023BBA000031 1 REA002407 REA001710 BBA001023 BBA000031 1 REA001423REA001710 BBA001023 BBA000031 1 REA001828 REA001906 REA002449 REA0020361 REA001416 REA001917 REA001557 REA000798 2 BBA000029 REA001936REA002446 REA002067 1 REA002420 REA002411 REA001829 REA002088 1REA001329 REA002438 BBA000029 REA002042

The building block combination X-REA001710-BBA001023-BBA000031 (X can bedifferent position A building blocks (reactants)) corresponds to ligandswith Ki values against human thrombin in the low nanomolar tosubnanomolar range (Tucker T J et al. J. Med. Chem. 1998, 41,3210-3219):

TABLE 2.2 Layout of tags (A, B, C, and D) and anti-tags (Ax, Bx, Cx, Dx)showing codons (XXXXXXXXXXXXXXXXXXXX). The specific nucleotide sequencesof overhang sequences are shown. A XXXXXXXXXXXXXXXXXXXXCCTAGGACCA BXXXXXXXXXXXXXXXXXXXXGTGTCACTTA C XXXXXXXXXXXXXXXXXXXXGTGCACGTGT DXXXXXXXXXXXXXXXXXXXXGAATTCTACTCTCCTCAAGGTGATCCA TGATGATGTTCCTT AxXXXXXXXXXXXXXXXXXXXXCATGAATTCTTGGTGACTTG BxXXXXXXXXXXXXXXXXXXXXTGGTCCTAGG Cx XXXXXXXXXXXXXXXXXXXXTAAGTGACAC DxXXXXXXXXXXXXXXXXXXXXACACGTGCAC

TABLE 2.3 Examples of specific tags and antitags. Both codon andoverhang sequences are shown. Tag Sequence A-0001pTGTTGTCCATGATGCTTCCTCCTAGGACCA A-0002 pCAACTTGATCTCCAGTCGTCCCTAGGACCAB-0001 pCTAGTGGTCGAAGTTGCACAGTGTCACTTA B-0002pCCTACGTCTTCATGGACCTTGTGTCACTTA C-0001 pTTCGTCCATGCACATGATCTGTGCACGTGTC-0002 pCAGTTCCTCCAAGCAGTAGGGTGCACGTGT D-0001pGTTCATCGTCTTCTAGGTGCGAATTCTACTCTCCTCAAGGT GATCCATGATGATGTTCCTT D-0002pTGAGGTTCGAGGTTGACGATGAATTCTACTCTCCTCAAGGT GATCCATGATGATGTTCCTT Ax-0001AGGAAGCATCATGGACAACACATGAATTCTTGGTGACTTG Ax-0002GACGACTGGAGATCAAGTTGCATGAATTCTTGGTGACTTG Bx-0001TGTGCAACTTCGACCACTAGTGGTCCTAGG Bx-0002 AAGGTCCATGAAGACGTAGGTGGTCCTAGGCx-0001 AGATCATGTGCATGGACGAATAAGTGACAC Cx-0002CCTACTGCTTGGAGGAACTGTAAGTGACAC Dx-0001 GCACCTAGAAGACGATGAACACACGTGCACDx-0002 ATCGTCAACCTCGAACCTCAACACGTGCAC “p” denotes a 5′ phosphate

TABLE 2.4 Building blocks (reactants) and their corres- ponding tagcodons used in the library synthesis. BB A Tag A codon BBA000029GTGCTACTGAGATGTTGCAG BBA000890 GCTGATGAGTTCGAGTTCTA REA000250GGTAGCAAGATGGTACTACG REA000778 CCACGACATCAACCATGGTG REA001143GATCACCTGTCGATGAACGA REA001329 TCTACGTTCACAGATGCTCG REA001398TCATGGTCTGCACTCAGGAT REA001399 CCTGTACCAACTGGACATCG REA001403TGCACTGTACGAGCAGGTCT REA001405 TAGGTCAGGAGTACAACACT REA001410CTCGTTGTCCAACATCACAT REA001411 CACACGATGCTGTAGCTCTA REA001415GAACTCTAGGTGGAAGGAAA REA001416 TACTGCATGTACCACCATGA REA001419ACAGGAAGACGTGCATGTAC Blank TGGTCTCGTTCTCGTCACAG REA001422TACAGAAGCATCGAGTAGCT REA001423 GGTCCTCTCAAGATGTGGAA REA001424GTGGTGAGCTTGTGGTCGAA REA001425 CGAACCTCCAGTAGCATGGT REA001426CCGATCCACGAGGAGCAAGT REA001446 ATCATGCAACCTACGAGCTT REA001464TTGGAGGTACGATCCACACA REA001767 CTGCTTCGTACCACAAGCTC REA001769TCACCACTTCCAGATCGTTC REA001773 CTCTTCAACCTGAGAACAAC REA001774TGTGGTGGTGCTCGTACTGC REA001775 CGTTCCTCTCAGAACCAGAG REA001780TGGAAGCTACCATCTCGTGC REA001781 GTGGATCGACCTCTAGCAAA REA001782CCAGTGCTAGGTTGCTCGAC REA001785 CAAGTTCTTGCACTCGATCT REA001792TACTGGACGACGTACTAGGC REA001793 CCTAGACGAGCTTCTGGTTG REA001798ACAGTCTCATGGTCCAAGTC REA001799 ACAGCACCTCGTGTAGGACT REA001800ACTGCAAGGATGCATCTGGC REA001801 CCTTGACACCAACGTGAAGT REA001803AGGAACCAGCAACGAGGTTA REA001805 TACTCCTCAGATCGTACGAA REA001806TTGTCTGAGGAGCTTCAGGA REA001807 CGTCGTCGACGATCCTCCAA REA001808CACCTTGTCAGGAGTACGTT REA001809 CAGTTGTACGAGGTTGCAGC REA001810CGTACCTTCTTCTAGCAACA REA001811 AGCTCCAGCTTCGAAGTTGA REA001813CTCATCCACTTGTGTGACGC REA001817 ATGGATGGTCCTACCTTCTC REA001818TGTTCCAGGACGTCCTGCAC REA001821 TACCTCGAAGGTCTGGATCG REA001823TGTTCTAGTGGAACTCAACG REA001824 AGTTGAACCATGCACTCTCT REA001827GAACTGATGTGCAAGAGTCT REA001828 GATGGTACCAACGACCTACA REA001830CAACACGACACATCCAACCT REA001833 GATGTGCTCTGCACACCAGC REA001834CCAGTAGAACACTAGAAGCG REA001836 AGATCGAAGACGAGTGAGTG REA001837GTAGGAGAGGTTCGATGGTG REA001838 ATCCATGTCTGGATCAGCAA REA001839GGTGCTCCAGAACGTACTTT REA001840 GGTAGGTACGTTGTTCTCCT REA001891GTAGCTTGCACTGGACGTCC REA001892 CCACTTGTGTTCCACTGATT REA001893CGAAGAGGTGGAACGACCAA REA001894 GTTGGTCGATCGAGTCCAAG REA001895TGTCCTTGTTGCACTCCTTA REA001897 CACATGATGTTCTCCTTGGT REA001899AAGTCTAGTCACACGACACC REA001902 GACCTAGCATGCTTCCTAGT REA001903AGACACGTTCGTGGTCGAGA REA001907 CATCCAAGGTCTGGTCTCTT REA001909AGGTTGAAGGTGCAACATGC REA001910 CCTGAGTGGTCCTTCTTGAA REA001911ACCTAGATGCTAGGAAGCAG REA001913 GTAGACAAGTACCACTGGTC REA001914GCATGGAACTTCCTGCAGGG REA001916 GATCAGGACTGGTTGGAAGG REA001919GGACAGAAGGATCTTCAGCC REA001924 ATCTGAGTTCCTTGGTTCTC REA001930AACTCGTGTCGTCTCCTTCT REA001933 TCTGTGAACATCCACCTTCG REA001934ATGTCGATGTAGTGGTCCTC REA001935 GCAGTTGAACTCCACGTTGC REA001937ATGTAGAGTGATGAGCTTCG REA001942 ACCAACGTCATCGTTGCTGA REA002406GACGTACAAGTTCTTGGACC REA002407 GTTGTAGGACCAAGCAAGCG REA002409TCGAAGTTCAGATCGTGATC REA002411 CTAGTGTGAAGTGGTCCATG REA002413GCAACAGCATCACAGATGTT REA002415 CGTTCTTGAAGCTACGACAG REA002419GTACCTGATCTGGATCTTGC REA002420 GGACTCTTCTCAACTGTTGT REA002422GAAGTGCTCGACATGGTCAC REA002423 GTACTAGGACCTTCGTTGCC Dummy AATCGTACAGACTCCTCACAG BB B Tag B codon Blank TTCGAGCTACACCTGCTGACREA001290 GGTCCAGCAAGAGCACCATA BBA001092 CTGGTCCTTCAGGAACGTAA REA001291TAGGTACCTGGTAGTGAAGT REA001464 GGTTGTTCCTGCTTGCTCAG REA001806CCAGTGGACTGACCTTGTGC REA002437 CGTGGTTCATGGAAGCAACG REA002438TCCTAGAGACATGCATGCAA BBA000008 CGAGCTGGATGCTACACTCA BBA001023GGTTCTCTACCTGAAGCTTC BBA001024 CCACTTGCAGTCTGTGGAAT BBA001025TGAACCAGGACACTGCTTGT BBA001091 AAGTGGAACTGGAGCACTAG BBA001093ATCCTCCTACTCCAGCTTCA REA000250 ACCACGTACTACCTAGTCTC REA000778GGTACTTGGATGGTGTTCGT REA001143 GGAACTTGAGTCCTTGATGA REA001280GAAGAGGTCGTAGGAAGGAA REA001281 GAGGTGCTTCGTCGTTGGTA REA001282GGAAGGATCTGGTACGTCCA REA001284 GCAAGTTGTAGCATCAAGGA REA001285CAAGCAGACGATCAAGGATT REA001286 CCTCATCTCTCTCTGGTCAC REA001313TCGTAGCATCCAGCAACAGT REA001315 TCGAAGGTCGTTCACCAGTG REA001334AACGATCACAAGGAGCAGTC REA001335 CACGACTAGCAACTCATGGC REA001336CTTGTGTCCACGAAGAACAT REA001337 CTAGAGGTGGTCCTCCTGTA REA001398GAAGTAGAACGATGCAACGG REA001399 TACGATGCACACTTGGTTGC REA001403GATCACAGGATCATGTTGGC REA001405 TGCATGAGAGACATGGAGAT REA001414CGTTGTGCATGTACCAAGTG REA001417 TGTGTACCTAGCTGCTTGGG REA001419TCTCCTGTGGAAGCAGCAGT REA001557 TAGCACTACGTGATCTGAGA REA001558GTCTTGAACTGATCCTACAG REA001710 GCAGCTGCAGCAGTCGTAGT REA001771TTGCTTGGAGAGTGTCACTG REA001785 GGAGTGGTTGGTGAGAGAGA REA001790AACGAAGGTTCTGCTCTGGT REA001801 AGTCCATCTGCTCGTAGCAT REA001804CGTGCTCCAAGCAGTAGCTG REA001824 GTCTGATCCTACCTTCCATA REA001828AAGTTCTCCTGATGCTCATC REA001833 CTGATCCACTGAGCACTTCA REA001840ACGTTCCAAGTCGTCATCGG REA001841 GGTCACGATGCATCCTGACA REA001842TCGTAGCAAGTGAGGAACAG REA001845 GGTGCTTGGTACGAACGTCG REA001846CTCGACCAACCTGACCTGAA REA001847 TTGGATCGACAGGACCTTCT REA001848TACTTCGTCCAGTTCCTTGC REA001849 ATCCTCTTGCTGTCAGTCGC REA001850GGTGAAGTACGACAACTACT REA001853 TCGTACCTGTCTTGTGTACC REA001855CTGGATGACCAGAACTTCAT REA001860 GATCGACTTGCAGACGTGCA REA001861AGCTACGTGAGAGAAGACAC REA001865 AGTCTGGTGGTGACGACTTT REA001891GCTAGGAGCACCATCACGAT REA001895 TGAGAAGGATCTCGTACCTC REA001901TAGCATCGTTGCTCCAGACA REA001903 AAGAACTCTTCGACTCCAAG REA001906ACGTAGTAGAGCTACAAGTC REA001910 CGTCCTACCAACCAAGCTAT REA001911GTTGCTCCTCCTTCTCGATT REA001912 GACAACTGTCCTCGTACACT REA001916GCATGAGAACTCTTGATCCA REA001917 CCTCCATGCTGAAGTGGAAA REA001918GGTACGACCATCAGTCCACC REA001920 TACAGTTGTCTCTGGTCTTG REA001931ACCTTGAACAACGACTCCTG REA001932 GACCAAGTCAGTGCAAGAGC REA001933CTACACAAGTGCTAGTCTTG REA001936 GTCTGCTGTAGCAACTCATC REA001937ACTGCTCAAGAGATCACTCA REA001940 GATCCACACGTTGCACGTTC REA001942AGACCTCCATCGATGGTAGG REA002341 TGTTCTCACAGCTTCCTACA REA002342ATCACAAGGAGATGGTTCTC REA002343 CACCTTGCACCTTGCATCAC REA002344TGTTGTCGAGTCCTCCAACT REA002345 ATCCACACCACGACATCTAA REA002346CATGTGAAGAACCTCGTCCC REA002347 TCTCCTGTCCAACAGTCCTT REA002348GTTGGACAGCAACCAGTGGT REA002349 GTAGGTACAGGTGAGGTACT REA002350AAGATGAGGAGTGCAGTACA REA002351 TACCTTGAAGCACGATGGAA REA002362ATCATGTCCTTGGATGGACT REA002363 GATGCTGATGAGTGCAACTA REA002408TACGTCAACGTAGATGGTGA REA002410 CGATCTGACAGTCCAAGGTA REA002411CCACGATCTCCTACAGACTT Dummy B CCTCGTCCTGATGTTGCATC BB C Tag C codon BlankCCAACTTGGAGGTTCATGCG REA001415 TTGGTTCTGACACTGTAGAC BBA001092ATCAACCTAGCACCAGGAAA REA001332 TTCTCACGACAGCAACCTTG REA001938CTCTCTTGCAGCTACTGAAT REA001939 AGTCAAGTCAGAGTTCGTAC REA001944TAGATCGTCACTGACGATCC BBA000008 GGACGTGAAGGACATCACAG BBA000029CACTACTTGTTCTACGTGCC BBA001023 ATCGTTCCAGTCGAGTTGAT BBA001024ATCAACCACCTCTACCACCG BBA001035 AAGCTACAACAGCAGCTACG REA000250CCAGTAGGTGATGCAACGTA REA000772 AACAGGTCCACAACAGATGG REA000778CCATGTCGTAGATCGTTCAC REA001143 TCATGTCTCGTAGACACTGC REA001281GAGGAAGCACAGCATCCATA REA001282 GCTGCTTCTGAGGAGGATCC REA001284GCAACAGAACTACATGACCG REA001315 GGACAGCTTGGATGCTTCAT REA001331ACCTAGTGGTACATCTTCCT REA001334 CGTGTAGAACCACGTTCGAC REA001337GTGCTACCAGAAGGATGCAA REA001407 CCACACAGGTCTCCTACATG REA001414GTTGAGTCGATCCAGAGTAG REA001421 GGTTCCTTCCTGAGGTTCGA REA001552ATCGTCCAACGAAGCAAGTT REA001557 AGTACGTTGCTAGTTGACGC REA001558GGACCTACCTTGCATGAGGA REA001768 GATCGACTTGAACTTCACCC REA001779TCAACGAACACCTGTCCACG REA001780 GGTGAAGCAAGTGTTCAACT REA001785GCTAGATGTGAAGGTCCTAA REA001790 AAGACAGTACCACGATGCTA REA001793GTTCGTACCACCTTCAAGAC REA001801 TGGAGTCGTACAGAAGCATG REA001815ACCTACAGTACCAGGTGGTG REA001824 CGAGACTGTTCCTGCACTCC REA001828TACTCTGCACGTCAGTTGTA REA001829 GCTCCTGATGTCCTGGTTGC REA001833TCCACATCCAGCTCGTGGTT REA001838 CGAGCACCAAGCACTGTTGT REA001840AAGGAACCACAACCAACCTG REA001841 GGATCCATCGTCTACCTCTA REA001845AAGATGGACTCTGCAACGTT REA001851 TACTGACACTCGTTGCTAGA REA001852ATCTGATGGATCTGTGCTCC REA001853 ACGAGTCTCTCCTAGGACAA REA001854TCGTTCTCGTACTTGTTGGA REA001855 GCTTGTCTAGACGTTCTCTG REA001856TCCTGCTTCAACCTAGATGG REA001857 GACTACCTGGATCGTACATA REA001858AAGCAAGGAGGTGTACGTTT REA001859 CCTGAGCTCAGAGTGTAGCC REA001860AGTGAGTCCTACCAAGCATG REA001861 TACGAGTGTGCAAGCATGTA REA001863CTCTTGACGTGTTGTGCTAG REA001864 AGGAGCAAGCAAGGTACCTT REA001865CGTGTGCAGAGGTTGCTGAA REA001892 CCTACTAGCAACCATGGTCG REA001893CTCACATGGTAGCACGATGC REA001896 CACTTGTACGAGAAGATCAG REA001901CGTTCCACTCATCTGTGCTT REA001902 CCTTCACGATCCTACAGTCA REA001905ATCTCAGACACCTTGATGTG REA001906 TCAGGTCTTGGTAGGATCCT REA001907TACGTCCTACCAGTCCACGA REA001909 CCATGCTACCAGTACCACTG REA001916GGACCTTGCTTCCACACGTC REA001917 CACCTGACTAGACAACAACT REA001918TTGGTCGAAGGAGTCGTGAC REA001920 TGCACCTGCACTCACGTCCT REA001923ACAGGAGCAAGGAAGCAACT REA001931 AACTGGAACTCAAGACAGAC REA001932GAAGCTGAGACCATGAGAAT REA001933 CTCGAAGTAGTGTTGATGGC REA001934CCATCCTCGATCTCGTGTTA REA001935 AGTCCATCTCGTGGAACTTC REA001937TGCATCCATCATCACTAGGC REA001940 TAGATCCTGTCAAGGTTGCC REA001945GCTTGGACTGTGCTGATGCG REA001946 CGTAGTAGACATCTCTAGCA REA001961ACTGTTCTCGATGCTAGTAC REA002341 CTCTTGTCAGACGTGCTTCG REA002344GCAGAAGTAGACTGTCCACG REA002345 TCGAGTGTGTGTACCAAGAC REA002351TTGGATGCAGTCCAGGAGAA REA002407 CATCTCCAGTGTCGAGCATG REA002409TACGTGACAAGGATCTTCGC REA002411 TGACCATCACCTTCTGCATT REA002416AAGCACAAGCACTGAGTCGG REA002444 TCCTGTCACTCCAACCTCGG REA002446ATGGAGAGTAGTCTCCTGGT REA002447 AAGAGATGCTGACTGGTAGG REA002448TCTCTCAAGCTACGTTGGAC REA002449 ACCTTGGAAGTACCAAGTTG Dummy CCGTGCTACCACACTCACAAT BB D Tag D codon BBA000895 TAGTGGTTCACGTGACCTATBBA001041 ATGTAGTCATGCTGTCCACT REA000894 CCTTCCAGTACATGCACTAT BBA000100GATCCTCCTTGTACCTAGTG BBA000139 TGAGGTACCTTGTACTCTCA BBA000837ATGGACGAGTCTGACGTAGC BBA000849 TTCGTTGAGGAACCTCACGG BBA000893CTCATGGTTCCTCCTACTGT BBA000894 GTGTTCGTTGGTGACTCGTG BBA000903CTGTGGAACGATGGAGGAGG REA000194 GCTCTTCCTTCGTCCTTGAT REA000892CCTACGATCCACGAAGCTTC REA001101 GGATCTACCAGCTTGTCTTA REA002259ATGCAAGTTGGTGCTGACTC BBA000031 TACAACGTCGTGTAGTCTCC BBA000820GCAACTACCTGACCAACCAT BBA000828 GCACGAAGATGTCACTGGTT BBA000829GGTTCCAAGTGTAGGAACGC BBA000830 TCCAACCAGCTCCTGGTACA BBA000836ACCTAGCTCACAAGGTGGAT BBA000843 AACTTGTCCTAGACTACGAG BBA000845ATCAGGTGTACGACTCAGTG BBA000846 CAGAAGCAACCAGTGGTCAC BBA000847TGACCACGTGGTAGGTCAGA BBA000851 CGTCGTACTTGTTGCACGTT BBA000852AGTGACACGACATGCACGAA BBA000853 CGACACTCTTGTAGTCGTGC BBA000862GGTTGGATCTCTCTGCTCTC BBA000886 TAGGTAGCAACCAACGACGT BBA000891ACCATGGTCCTCCTGGAGAT BBA000892 AGGATCCTCTTCAGCACTGT BBA000896GCAACTGGAGTGTGATCCAC BBA001038 GACAGGTCATCAGTCGTTGC BBA001039GGACTGTGAACGTACACCTC BBA001042 ATCCTTCAGTACGATCCATC REA001095TGATGATCTGTGGACGATCT REA000068 ACGACTCCAACTGTCCTGGC REA000402CCTTCATCTGGAGATGTCGA REA000556 TGGTAGTTCCTTCAGGAGTC REA000736AAGAAGCAGTCCTAGCACGG REA000749 TGCTGGTAGACAAGACGATT REA000893AACTCTTCGACGTGACACTC REA000898 AACAAGACGTGACGTTGCTG REA000901GATCTCTTGAGTGGAGTCCC REA001004 CACCAACCTCAGACCTGAGA REA001015GGATGCACAGGTACAGGAAT REA001022 TACCACAACCAGTCCTTCCT REA001023ATGCTGTCAAGCTTGTAGGG REA001028 CTTGCATCAAGCATCGAGCG REA001029AGGATCCTGTCACTAGTGGA REA001031 CTGCAAGCTAGACAACAGTG REA001038CGACCTCCACTGGTAGACCT REA001044 TCCAAGACTACGATGTTGAG REA001045CCTCTGATGGTTCATCCAGT REA001055 GATGAGACATGCTACAAGAG REA001056GCTGGAGGTGTTCATCAACA REA001058 TGGAGTTCGAGTACGAGTCA REA001061AGTTGCAGACAGGATGAACG REA001062 GTAGTGAACGACCACGAGTG REA001069TACGTCGTCCTTGCAGACAA REA001070 GTACAGGATCTACGTTGAGC REA001071GTGCTCAACAGTCAGGTGCC REA001072 GCTTCGTACGATCATGTACC REA001085GGTGTGTTCAGAACAAGCAC REA001090 CTCGATGGAGGTTGTAGCAC REA001093TAGCACGTTGAGCTACGATC REA001094 ACAGCAAGTTCGTTCCTCTA REA001097TGTTCGTTGTCAGCAGTTCG REA001100 TCATCGAGCAAGGTGTTCGC REA002260CGAGTCTTCAACTTCCAAGC REA002262 TCCATGTTCGTACGACGATG REA002264GTGTACTCCAGACTTCCTTT REA002275 TACTTGCACCAGACTTGTAC REA002276AGTACAGGACAAGACACGTT REA002279 CGATGAGAGTAGTGTCTACG REA002284GCAAGCTCAGAGCAGAAGTG REA002292 CGTGACACGTGTTCAGCACG REA002298GTACGTGTTGCACAAGAGCA REA002299 ACGATCACTACGATGAAGGT REA002301TAGGACGTAGCAGACAACTA REA002303 TCTCAGTACGTTCGTAGTCT REA002305GCAAGCAACTTCGTTGGTAC REA002307 GTAGAGAGACATCCAACCAA REA002310CCTGCTAGTGCTTCCTTGGG REA002312 CACACGATCTGTAGTCCTGA REA002313ACACCAAGGTTCAGATGTGT REA002323 TTCTACTGCTGTTGACCTTG BlankCCTGTCATCCTTCGTACTAT REA001966 GTTCGAACAAGTCTCCAGAG REA001969GGAAGGACCAGACTGTCACG REA001970 ACCTACAGACACACAGATGC REA001973TTCTGTAGGACCTTGGAACT REA001978 GCTCCATGGATGTACCTTCA REA001986ATCCTCTCCATGCTAGAGGT REA001989 GAGAAGGAGAAGGTCGTTGC REA002000TACGTGAGTAGCTACTGGAA REA002003 TAGGAGTACTCCAGGATCGC REA002004TCAAGTGTCTGACGAAGCTA REA002009 GTGATGGTAGACAGCTGTAA REA002016AAGTGGAGTTGGATGCACCT REA002019 TTCCTGGTTGGACTCGTCGG REA002020CCTGCACGAACACTTGCACA REA002027 TGAGTTGCTGCACTGTTGCT REA002036CTTGTCAAGCAGTCACTAGA REA000798 TCACATGACCAGCACGTGCG REA001466CGATCAAGCTACAGAAGAAG REA001475 TGGACTCTGTCGAAGGTACA REA001508CTGTAGCATCCACTCCATCC REA001646 GACTGTGGTGACACCTGACT REA002038GCTTCGACAGACATCACTCG REA002042 ATGGACAGTGGACACTCATT REA002046GCTTCTCCTGGTTGATGGTC REA002050 CGTGGAAGGTTGAGCTCAAC REA002065ACATCTAGTCCAGGTGGTTT REA002067 CCTCGAACCTTGCTACAGCG REA002075CGACGAGCACACTCTCTCAG REA002076 ATGCTTGCACTGTGATGACA REA002077GTGTACTGAGTGCAGCATGG REA002086 TACGAGCAAGGTAGCTGGTG REA002088CGTTCTAGGAAGTGAAGCTG

TABLE 2.5A Position A building blocks (reactants). The unprotectedstructures are shown. The amines were protected by Fmoc groups duringloading. After loading Fmoc groups were removed.

TABLE 2.5 B

TABLE 2.5C

TABLE 2.5D

Example 3 Bifunctional Complexes Containing One or More DisplayMolecule(s) and One or More Identifier (s)

A library is synthesized as described in example 2. At a stage where thebifunctional complexes containing a display molecule (D) are purifiedand have single stranded identifier oligos, an anchor oligo containing adisplay molecule (R) is annealed to the single stranded identifieroligos:

Then an extension oligo (b) is annealed to the single strandedidentifier oligo of the bifunctional complexes. The extension oligo isthen extended with an enzyme that does not displace or degrade theanchor oligo. The library is then used for selection. Using anchoroligos with different display molecules (R) it is possible to modulatethe average affinity of the library.

Alternatively the following display oligo is used during librarysynthesis:

The display oligo contains one or more (n) of chemical reaction sites(R), one or more branching linkers (B), one or more (m) chemicalreaction site(s) (Y) protected by a protection group (P). Using thisdisplay oligo a library of bifunctional complexes is synthesized asdescribe in example 2. The resulting bifunctional complexes contain oneor more display molecules (D) and one or more (p) identifiers (i):

The protection group (P) is then removed allowing a molecule (M) to belinked to Y:

Thus, properties of the bifunctional complexes, such as affinity for atarget or target site, solubility etc. can be modulated by attaching tothe chemical reaction site (Y) one or more molecules (M) which conferthe desired property onto the bifunctional complex.

Example 4 Synthesis and Affinity Selection of a Library Encoding on theOrder of 65.000 Scaffolded Compounds Employing Quenching of Reactants

A library on the order of 65.000 DNA-tagged small molecules issynthesized using the building blocks (reactants) and tags described inexample 2.

900 pmol Display oligo is added to each of 16 wells. In each well thedisplay oligo carries a specific building block (position A buildingblock).

Ligation of A-Tags

10 μl buffer (120 mM HEPES pH 7.8, 40 mM MgCl2, 40 mM DTT and 4 mM ATP)is added to each well. 500 μmol double-stranded A-codons (e.g., thecombination A-0001 and Ax-0001) is also added (See table 4.4A for tagsand corresponding building blocks (reactants)). Annealing was thenperformed by a 80° C. to 20° ramp in a PCR machine (EppendorfMastercycler Gradient). In one well 50 pmol double-stranded 5′ phosphate32-labeled A-codon is added. 1 μl of T4 DNA ligase (20 U/μl) is added toeach well. Samples are then incubated in a PCR-machine with thefollowing temperature profile: 25° C. for 10 min, 45° C. for 10 min, and25° C. for 10 min. The ligase is inactivated by incubating samples at68° C. for 10 min. 25 μl of water is then added to each sample. To allowverification of the efficiency of the following dephosphorylation step,a “Dummy A” codon labelled with 5′ phosphor-32 is added to a sample. Athermostable phosphatase is then added to each sample and samples areincubated to remove free 5′ phosphate groups. The samples are thenpooled and precipitated using 0.05 volumes of 5 M NaCl and 50%isopropanol as described in example 2.

Ligation of B-Tags

The sample is dissolved in water and distributed equally to 16 wells. Toeach well 750 pmol double-stranded B-tags is added and ligation anddephosphorylation is performed as described for the ligation of A-tags.After ligation and inactivation of the enzyme, the samples arelyophilized.

Load of Position B Building Blocks (Reactants)

Each sample is dissolved 5 μl 200 mM Na-phosphate buffer pH 8.0 or 100mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0 according to previouslyidentified reaction conditions. To each well is added add 4 μl solutionof a building block (100 mM in dimethyl sulfoxide). For each well 0.72μl 0.5M DMT-MM solution in water is mixed with 0.28 μl 200 mMNa-phosphate buffer pH 8 and added to the well. The wells are thenincubated at 30° C. for 16 hours in a PCR-machine (EppendorfMastercycler Gradient). Then an appropriate quenching reagent, e.g.piperidine, is added to each sample to ensure that all reactive speciesare rendered unreactive. The samples are then pooled and precipitatedusing 0.05 volumes of 5 M NaCl and 50% isopropanol and washed with cold70% ethanol.

Msec Deprotection

Primary amines of position B building blocks (reactants) are protectedby Msec groups:

Msec protection groups are removed by dissolving the material in 25 μl0.1 M Sodium Borate Buffer pH=10 and incubating at 40° C. for 3 hours.Then the material is lyophilized and dissolved in 85 μl H₂O.

Ligation of C-Tags

In each well ligation of double-stranded C-tags were performed asdescribed for A- and B-tags.

Load of Position C Building Blocks (Reactants)

Samples to undergo isocyanate addition are redissolved in 8 μl buffer(100 mM sodium borate and 100 mM sodium phosphate pH 8.0) 1 μl of aspecific building block (300 mM in CH₃CN) are added to each well andincubated at 50° C. for 16 hours in a in PCR-machine (EppendorfMastercycler Gradient).

Samples to undergo sulfonylation were dissolved in 8 μl 100 mM SodiumBorate buffer pH 9. Then, 2 μl specific building block (100 mM intetrahydrofuran) was then to each well and incubated at 30° C. for 16hours in a PCR-machine.

Samples to undergo acylation were dissolved in 5 μl 200 mM Na-phosphatebuffer pH 8.0 or 100 mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0.Then, 4 μl specific building block (100 mM in dimethylsulfoxide) wasadded to each well. Then 1 μl DMT-MM mix (0.36 M DMT-MM in water and 56mM Na-phosphate buffer pH 8) was mixed in each well and the sample wasincubate at 30° C. for 16 hours in a PCR-machine.

Then an appropriate quenching reagent, e.g. piperidine, is added to eachsample to ensure that all reactive species are rendered unreactive. Thesamples are then pooled and precipitated using 0.05 volumes of 5 M NaCland 50% isopropanol and washed with cold 70% ethanol

Desphosphorylation

Dephosphorylation is performed as described for A-tags. The sample isthen precipitated using 0.05 volumes of 5 M NaCl and 50% isopropanol andwashed with cold 70% ethanol.

Ns Protection Group Removal

Secondary amines of position B building blocks (reactants) are protectedusing Ns:

To remove the Ns protection group, the material is applied to DEAE(which had been washed 2 times with 10 mM Aq. AcOH), then the materialon DEAE is washed with water followed by washing with dimethylformamide. Then the material on DEAE is incubated in a solution of 0.5Mmercaptoethanol and 0.25 M DIPEA in dimethyl formamide and incubated for24 hours at 25° C. in an eppendorph thermoshaker at 600 rpm. Then thematerial on DEAE is washed with 0.3M AcOH in DMF, then twice with DMFand then with water. The Ns-deprotected material is then released fromDEAE by adding 70 μl release solution (1.5 M NaCl) and incubating at 25°C. for 10 minutes in an eppendorph thermoshaker at 600 rpm. Water isadded to the material to a final NaCl concentration of 0.5 M. Then thematerial is precipitated by adding one volume of isopropanol asdescribed.

Ligation of D-Tags

D-tags are ligated as described for A-B-, and C-tags. Then samples werepurified using gel-filtration as described and lyophilized.

Load of Position D Building Blocks (Reactants)

Samples to undergo isocyanate addition were redissolved in 8 μl buffer(100 mM sodium borate and 100 mM sodium phosphate pH 8.0) 1 μl of aspecific building block (300 mM in CH₃CN) was added to each well andincubated at 50° C. for 16 hours in a in PCR-machine (EppendorfMastercycler Gradient). Then, 40 μL of water was added to each sample.

Samples to undergo sulfonylation were dissolved in 8 μl 100 mM SodiumBorate buffer pH 9. 2 μl specific building block (100 mM intetrahydrofuran) was then to each well and incubated at 30° C. for 16hours in a PCR-machine. Then, 40 μl of water was added to each sample.

Samples to undergo acylation were dissolved in 5 μl 200 mM Na-phosphatebuffer pH 8.0 or 100 mM Na-Borate pH 9.0 or 100 mM Na-Borate pH 10.0.Then, 4 μl specific building block (100 mM in dimethylsulfoxide) wasadded to each well. Then 1 μl DMT-MM mix (0.36 M DMT-MM in water and 56mM Na-phosphate buffer pH 8) was mixed in each well and the sample wasincubate at 30° C. for 16 hours in a PCR-machine. Then, 40 μl of waterwas added to each sample.

Samples to undergo reductive amination were dissolved in 15 μl 200 mMNaOAc buffer pH 5.0 5 ul specific BB was added to each well (200 mM inDMSO) and incubate at 30° C. for 1 h. Then 5 μl of freshly prepared 140mM NaCNBH3 (REA000025; 8.8 mg/ml) in NaOAc buffer pH 5.0 to was addedeach well and the samples were incubated at 30° C. for 16 hours in aPCR-machine (Eppendorf Mastercycler Gradient). Then 25 μl of water wasadded to each sample.

Samples to undergo nucleophilic aromatic substitution were dissolved in12 μl 100 mM Borate Buffer pH 9. Then 12 μl specific BB was added toeach well (100 mM in DMSO) and all wells were incubated for 16 hours at90° C. in a PCR-machine (Eppendorf Mastercycler Gradient). Then 40 μl ofwater was added to each sample.

Then an appropriate quenching reagent, e.g. piperidine, is added to eachsample to ensure that all reactive species are rendered unreactive. Thesamples are then pooled and precipitated using 0.05 volumes of 5 M NaCland 50% isopropanol and washed with cold 70% ethanol

Fmoc Deprotection

Samples are redissolved in water and adjusted to 6% piperidine. Samplesare then incubated at 25° C. for 30 minutes to remove Fmoc protectiongroups. Samples are then again precipitated using isopropanol.

The combined material is redissolved in water and adjusted withpolyacrylamide gel electrophoresis loading buffer. The material iselectrophoresed and purified by isolating the material corresponding tobifunctional complexes with 4 tags. The single stranded bifunctionalcomplexes are eluted from the gel, precipitated using isopropanol asdescribed, and purified by gel-filtration as described.

Primer extension and affinity selection is the performed as describedfor examples 1 and 2.

Example 5 Synthesis of Bifunctional Complexes Containing a CleavableLinker and Release of Display Molecules

Bifunctional complexes are synthesized from an initial bifunctionalcomplex which contains a chemical reaction site linked with a cleavablelinker to a tag. If bifunctional complexes are synthesized in a parallelsynthesis fashion it is not necessary to add tags which encode thebuilding blocks (reactants) that are added at the chemical reactionsite(s). If bifunctional complexes are synthesized by a split-poolmethod, tags which encode the different building blocks (reactants) canbe added during synthesis as described in examples 1 and 2. Following asplit-pool synthesis the bifunctional complexes can then be sorted byemploying capture oligos which hybridize to specific codons in theidentifier oligonucleotides of the bifunctional complexes.

After synthesis and purification, the cleavable linker is cleaved usingappropriate conditions such as electromagnetic radiation, enzymes etc.For example, a cleavable linker such as:

can be cleaved using ultraviolet radiation. The released small moleculecan then be used in an assay to determine a property of the displaymolecule.

The bifunctional complex containing a DNA tag (T):

was synthesized employing the chemical reactions (acylation and Fmocdeprotection) as described in example 2. The bifunctional complex wasexposed to ultraviolet radiation (omnilux lamp E40, SteinigkeShowtechnic Germany) for 120 seconds to release the display molecule:

To determine the Ki of the released display molecule against theprotease thrombin, human alpha-thrombin (Heamatologic Technologies Inc.)was diluted in buffer (0.015 units/μl) and the released display moleculewas added. Following 5 minutes of incubation at 22° C. a chromogenicsubstrate (Chromogenix catalogue number S-2238) was added and themaximum turnover (Vmax) of the enzyme was determined in a by measuringthe change in absorbance at 405 nm using a Versamax reader (MolecularDevices). This was repeated for different concentrations of the releaseddisplay molecule and different concentrations of substrate. The Vmaxvalues obtained were then fitted using nonlinear regression implementedin the Prism software (Graphpad) to obtain the Ki of the displaymolecule. A Ki value of 5.2 nM was obtained (95% confidence interval:0-13 nM).

Example 6 Synthesis and Affinity Selection of a Library Encoding on theOrder of 1.100.000.000 Compounds

The first set of building blocks (reactants) were loaded onto a displayoligo (see FIG. 1.2).

The described general procedures were used in the following order:

Position A building blocks (reactants) and A-tags:R1-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

80 position A building blocks (reactants) were used. The building blockwere trifunctional with one free —COOH reactive group, one Ns-protectedamine and one Msec-protected amine.

Position B building blocks (reactants) and B-tags:R1-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

192 position B building blocks (reactants) were used

Position C building blocks (reactants) and C-tags:(R1/R2/R3)-P1-QC1-V1-T1-QC3-M 1-V2-D2-V2-P3-V2-S1-VI

88 isocyanate building blocks (reactants) were used

96 sulfonoyl building blocks (reactants) were used

200 acylation building blocks (reactants) were used

Position D building blocks (reactants) and D-tags:(R1/R3/R4/R5)-P1-QC1-V1-T1-QC3-M1-V2-P3-V2-D1-V2

88 aldehyde building blocks (reactants) were used

16 sulfonoyl building blocks (reactants) were used

24 halogenated heteroaromatic building blocks (reactants) were used

64 acylation building blocks (reactants) were used

Example 7 Screening of a Library Using Unspecific Elution

Biotinylated Renin was used as the target.

A fraction of the obtained bifunctional complexes was lyophilized anddissolved in 5 μl target buffer (137 mM NaCl, 2.7 mM KCl, 10 mM sodiumphosphate, 0.1% Tween-20, 0.1% BSA). 50 μl streptavidin sepharose(Amersham Biosciences) slurry was washed in 4×100 μl target buffer andresuspended in 50 μl target buffer. Then biotinylated target was addedto the streptavidin sepharose slurry and the slurry was incubated at 15°C. with agitation (1400 rpm) for 30 minutes and subsequently washed 4times with 100 μl target buffer. A 10XL barrier tip (AH diagnostics,Denmark) were prepared by pushing the tip filter approx. 5 mm towardsthe end of the tip. The tip was placed in a 1 mL pipette tip. Thetarget-loaded streptavidin sepharose was applied to the tip and washed 3times with 100 μl target buffer by applying vacuum to the bottom end ofthe tip. The library was applied to the column and allowed to soak in.Then the column was washed 5 times with 100 μl target buffer.Bifunctional complexes were eluted by applying 50 μl 1% SDS in H2Opreheated to 60° C. for 10 min followed by centrifugation of the column(1000 rcf for 30 seconds). An additional 25 μl PBS was applied to thecolumn and spun through. The eluted material was re-applied to a freshcolumn. This cycle was repeated 4 times. A 10 μl sample of elutedmaterial was used PCR using the forward and reverse primers5′-CAAGTCACCAAGAATTCATG and 5′-TCTGGTGGTCTACGTGCTCT. The PCR product wascloned and sequenced using standard methods.

Example 8 Synthesis and Affinity Selection of a Library Encoding on theOrder of 3.5e6 Compounds Based on a Triazine Scaffold

The described general procedures were used in the following order:

Position A building blocks (reactants) and A-tags:R1-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

96 position A building blocks (reactants) were used. The building blocks(reactants) were bifunctional with one free —COOH reactive group, oneFmoc-protected amine

The material in all wells were redissolved in 10 μl buffer (100 mMNa-carbonate pH 9.3). 10 μl 1,3,5-trichloro-2,4,6-triazine dissolved to200 mM in acetone was added to each well and incubated for at 4° C. for1 hour Position B building blocks (reactants) and B-tags:P1-R5-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

192 position B building blocks (reactants) (amines) were used. At the R5step the material in each well was redissolved in 10 μl 100 mMNa-carbonate pH 9.3 or 10 μl 100 mM Na-phosphate pH 8 and 10 μl buildingblock solution (200 mM in acetone) was added and incubated at 4° C. or25° C. for 1 hour or at 30° C. for 16 hours.

Position C building blocks (reactants) and C-tags:R5-P1-QC1-V1-T1-QC3-M1-V2-D2-V2-P3-V2

192 position C building blocks (reactants) (amines) were used. At the R5step the material in each well was redissolved in 10 μl 100 mM Na-boratepH 9.5 and 10 μl building blocks (reactants) (200 mM in DMSO) were addedand incubated at 90° C. for 16 hours.

Example of a structure generated by this method.

Position D tags: P1-QC1-V1-T1-QC3-M1-V2-P3-V2

No building blocks (reactants) were added at this step. The D-tags wereligated to diversify the bifunctional complexes such that several codoncombinations corresponds to the same molecule. 192 different D-tags wereused.

The library was screened on kinase p38 using unspecific elution andspecific elution using a p38 ligand. The identifiers were amplified andsubjected to ultra high-throughput sequencing. Ligands based oninformation deduced from the identifier sequences were resynthesized andtested in a p38 kinase assay. 15 ligands with nanomolar IC50 values wereidentified.

Example 9 Synthesis and Affinity Selection of a Second Library DesignedBased on Results Obtained by Synthesis and Affinity Selection of a FirstLibrary

A library encoding on the order of 110.000.000.000 molecules wassynthesized using the method described in example 6. Briefly,

The first set of building blocks (reactants) were loaded onto a displayoligo (see FIG. 1.2).

The described general procedures were used in the following order:

Position A building blocks (reactants) and A-tags:R1-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

576 position A building blocks (reactants) were used. The building blockwere trifunctional with one free —COOH reactive group, one Ns-protectedamine and one Msec-protected amine.

Position B building blocks (reactants) and B-tags:R1-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

576 position B building blocks (reactants) were used

Position C building blocks (reactants) and C-tags:(R1/R2/R3)-P1-QC1-V1-T1-QC3-M1-V2-D2-V2-P3-V2-S1-V1

96 isocyanate building blocks (reactants) were used

96 sulfonoyl building blocks (reactants) were used

384 acylation building blocks (reactants) were used

Position D building blocks (reactants) and D-tags:(R1/R3/R4/R5)-P1-QC1-V1-T1-QC3-M1-V2-P3-V2-D1-V2

96 aldehyde building blocks (reactants) were used

96 sulfonoyl building blocks (reactants) were used

96 halogenated heteroaromatic building blocks (reactants) were used

96 acylation building blocks (reactants) were used

96 isocyanate building blocks (reactants) were used

The library was screened using unspecific elution (example 7),identifiers were amplified and analyzed by ultra high-throughputsequencing. The sequencing revealed that identifiers containing thefollowing tag combinations had been enriched:

A523-B201-C341-D234 A523-B201-C341-D234 A523-B156-C341-D234A523-B156-C341-D142 A523-B201-C341-D142

(Tags A001-A576, B001-B576, C001-C576, and D001-576 were used forlibrary synthesis at positions A, B, C, and D, respectively).

Ligands corresponding to said enriched identifiers were synthesizedaccording to the method described in example 5. The affinity could notbe determined in an affinity assay indicating that the ligands hadaffinities lower than 10 μM in the assay.

However, a second library was synthesized including the reactantscorresponding to the tags in the enriched identifiers. Furthermore,reactants that were analogous in structure or function to said reactantswere also used for synthesize of the second library.

The second library encoded on the order of 110.000.000.000 molecules andwas synthesized using the method described in example 6. Briefly,

The first set of building blocks (reactants) were loaded onto a displayoligo (see FIG. 1.2).

The described general procedures were used in the following order:

Position A building blocks (reactants) and A-tags:R1-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

576 position A building blocks (reactants) were used. The building blockwere trifunctional with one free —COOH reactive group, one Ns-protectedamine and one Msec-protected amine.

Position B building blocks (reactants) and B-tags:R1-P1-QC1-V1-T1-QC3-M1-V2-D1-V2-P3-V2-S1-V1

576 position B building blocks (reactants) were used

Position C building blocks (reactants) and C-tags:(R1/R2/R3)-P1-QC1-VI-T1-QC3-M1-V2-D2-V2-P3-V2-S1-V1

96 isocyanate building blocks (reactants) were used

192 sulfonoyl building blocks (reactants) were used

192 acylation building blocks (reactants) were used

Position D building blocks (reactants) and D-tags:(R1/R3/R4/R5)-P1-QC1-V1-T1-QC3-M1-V2-P3-V2-D1-V2

96 aldehyde building blocks (reactants) were used

96 sulfonoyl building blocks (reactants) were used

192 halogenated heteroaromatic building blocks (reactants) were used

96 acylation building blocks (reactants) were used

The library was screened using unspecific elution (example 7),identifiers were amplified and analyzed by ultra high-throughputsequencing. The sequencing revealed that identifiers containing thefollowing tag combinations had been enriched:

A543-B203-C131-D236 A543-B203-C131-D236 A543-B158-C131-D236A543-B158-C131-D122 A543-B203-C131-D122

Ligands corresponding to said enriched identifiers were synthesizedaccording to the method described in example 5. The affinity of theligands were determined to be in the 1 nM to 10 μM range.

1. A method for the synthesis of a bifunctional complex comprising amolecule and a single stranded oligonucleotide identifier attached tothe molecule, said method comprising the steps of i) providing a displayoligonucleotide attached to a) one or more chemical reaction site(s)comprising one or more reactive groups and b) one or more primingsite(s) for enzymatic addition of a tag, ii) providing a first reactantcomprising one or more chemical entities and one or more reactive groupscapable of reacting with c) the chemical reaction site(s) of the displayoligonucleotide, and/or d) one or more reactive groups of at least afirst further reactant comprising one or more chemical entities, whereinsaid first further reactant is provided simultaneously or sequentiallyin any order with the first reactant, iii) providing a firstoligonucleotide tag capable of hybridising to part of a firstoligonucleotide anti-tag, wherein the first oligonucleotide tagidentifies the first reactant and, optionally, the further firstreactant, iv) providing a first oligonucleotide anti-tag capable ofhybridising to at least part of the first oligonucleotide tag providedin step iii) and to at least part of the display oligonucleotideprovided in step i), v) reacting the first reactant provided in step ii)with c) the one or more chemical reaction site(s) of the displayoligonucleotide and/or with d) the one or more reactive groups of thefirst further reactant comprising one or more chemical entities, whereinthe reaction of complementary reactive groups result in the formation ofa covalent bond, and wherein one or more reactive group reactions ofstep v) result in the formation of one or more covalent bond(s) betweenthe chemical reaction site(s) of the display oligo and at least onechemical entity of at least one reactant selected from the groupconsisting of the first reactant and the further first reactant, vi)hybridising the anti-tag to the display oligonucleotide and to the firstoligonucleotide tag, wherein method steps v) and vi) are simultaneous orsequential in any order, vii) enzymatically ligating the displayoligonucleotide and the first oligonucleotide tag, viii) providing asecond reactant comprising one or more chemical entities and one or morereactive groups capable of reacting with c) the chemical reactionsite(s) of the display oligonucleotide, and/or d) one or more reactivegroups of one or more reactant(s) having reacted in a previous synthesisround, and/or e) one or more reactive groups of at least a secondfurther reactant comprising one or more chemical entities, wherein saidsecond further reactant is provided simultaneously or sequentially inany order with the second reactant, ix) providing a secondoligonucleotide tag capable of hybridising to part of a secondoligonucleotide anti-tag, wherein the second oligonucleotide tagidentifies the second reactant and, optionally, the further secondreactant, x) providing a second oligonucleotide anti-tag capable ofhybridising to part of the first oligonucleotide tag provided in stepiii) and to part of the second oligonucleotide tag provided in step ix),xi) reacting the second reactant provided in step viii) with c) thechemical reaction site(s) of the display oligonucleotide and/or d) oneor more reactive groups of one or more reactant(s) having reacted in aprevious synthesis round and/or e) one or more reactive groups of afurther second reactant comprising one or more chemical entities,wherein the reaction of complementary reactive groups result in theformation of a covalent bond, and wherein one or more reactive groupreactions of step xi) result in f) the formation of one or more covalentbond(s) between the one or more chemical reaction site(s) and at leastone chemical entity of at least one reactant selected from the groupconsisting of the second reactant and the further second reactant,and/or g) the formation of one or more covalent bond(s) between areactant having reacted in a previous synthesis round and at least onechemical entity of at least one reactant selected from the groupconsisting of the second reactant and the further second reactant, xii)hybridising the anti-tag to the first oligonucleotide tag and the secondoligonucleotide tag, wherein method steps xi) and xii) are simultaneousor sequential in any order. xiii) enzymatically ligating the first andsecond oligonucleotide tags in the absence of ligation the first andsecond anti-tag oligonucleotides, and optionally xiv) displacingunligated anti-tags from the bifunctional complex comprising a moleculeand a single stranded oligonucleotide identifier comprising tagsidentifying the reactants which participated in the synthesis of themolecule.
 2. The method of claim 1, wherein the method of claim 1 isperformed in parallel in different reaction compartments, wherein thedisplay oligonucleotide of step i) is provided in each of a plurality ofseparate reaction compartments and subsequently, wherein, in each ofsaid reaction compartments, the first reactant and optionally also thefurther first reactant is/are reacted with the one or more chemicalreaction site(s), and wherein, in each of said compartments, a firstoligonucleotide tag identifying said one or more reactant(s) is addedenzymatically to the one or more priming site(s), said reaction(s) ofsaid reactant(s) and said addition(s) of said tag resulting in theformation, in each of said reaction compartments, of different nascentbifunctional complexes.
 3. The method of claim 2, wherein said differentnascent bifunctional complexes are mixed, and wherein said mixture ofdifferent nascent bifunctional complexes is subsequently divided into aplurality of different reaction compartments.
 4. The method of claim 3,wherein a different nascent bifunctional complex is provided in each ofsaid plurality of separate reaction compartments and subsequently, ineach of said reaction compartments, the second reactant and optionallyalso the further second reactant is/are reacted with one or more of achemical reaction site and one or more reactive group(s) of a firstreactant and/or further first reactant, and wherein, in each of saidcompartments, a second oligonucleotide tag identifying said one or morereactant(s) is added enzymatically to the first oligonucleotide tag,said reaction(s) of said reactant(s) and said addition(s) of said tagresulting in the formation, in each of said compartments, of furtherdifferent nascent bifunctional complexes.
 5. The method of claim 4,wherein, in each subsequent round of parallel synthesis, the reactantreaction product of a previous synthesis round reacts with the reactantin a subsequent synthesis round, and wherein a tag added in a previoussynthesis round acts as a substrate for the enzyme which adds a tag in asubsequent synthesis round. 6-12. (canceled)
 13. The method of claim 1,wherein the identifier oligonucleotide is amplifiable.
 14. The method ofclaim 1, wherein the display oligonucleotide has a length of from about3 consecutive nucleotides to about 25 consecutive nucleotides. 15.(canceled)
 16. The method of claim 14, wherein tag(s) have from about 3consecutive nucleotides to about 25 consecutive nucleotides. 17.(canceled)
 18. The method of claim 14, wherein anti-tag(s) have fromabout 3 consecutive nucleotides to about 25 consecutive nucleotides. 19.(canceled)
 20. The method of claim 14, wherein single-strandedover-hangs resulting from hybridisation of tags and anti-tags have alength of from about 3 consecutive nucleotides to about 25 consecutivenucleotides.
 21. (canceled)
 22. The method of claim 1, wherein theidentifier oligonucleotide resulting from tag ligation(s) has a lengthof from 6 to about 200 consecutive nucleotides.
 23. (canceled)
 24. Themethod of claim 1, wherein the identifier oligonucleotide comprises astring of consecutive nucleotides comprising from 2 to 10 tags. 25-37.(canceled)
 38. The method of claim 1, wherein end-positioned nucleotidesof anti-tags comprises no reactive group(s) capable of being linked byan enzyme comprising ligase activity.
 39. The method of claim 1, whereinthe one or more priming site(s) of the display oligonucleotide comprisesa 3′-OH or 5′-phosphate group, or a functional derivative of such agroup, capable of being linked by an enzyme comprising ligase activity.40. The method of claim 1, wherein molecule decoding or reactantidentification is performed by sequencing all or some of the nucleotidesof each tag of the identifier oligonucleotide. 41-42. (canceled)
 43. Themethod of claim 1, wherein the one or more chemical reaction site(s) ofthe display oligonucleotide each comprising one or more reactive groupsreact with one or more reactants each comprising one or more reactivegroups, wherein the chemical reaction sites can the same or differentchemical reaction sites, wherein the reactive groups can be the same ordifferent reactive groups, and wherein the reactants can be the same ordifferent reactants. 44-58. (canceled)
 59. The method of claim 1,wherein the reactive groups involved in the synthesis of a molecule areselected from the group consisting of carboxylic acids, alcohols,thiols, aldehydes, ketones, amides, imides, amines, azo, diazo, azido,hydrazines, carbamates, esters, thioesters, cyanides, ethers,isocyanates, isothiocyanates, sulfides, nitrites, nitrites, nitrates,nitro, peroxides, phosphates, thiophosphates, sulfides, epoxides,anhydrides, halides, acid halides, organometallics, nitrides,phosphides, carbides, and suicides.
 60. The method of claim 1, whereinthe reaction of the chemical reaction site and a reactant, or thereaction of different reactants, results in the formation of at leastone bond selected from the group consisting of peptide bonds,sulfonamide bonds, ester bonds, saccharide bonds, carbamate bonds,carbonate bonds, urea bonds, phosphonate bonds, urethane bonds, azatidebonds, peptoid bonds, ether bonds, ethoxy bonds, thioether bonds, singlecarbon bonds, double carbon bonds, triple carbon bonds, disulfide bonds,sulfide bonds, phosphodiester bonds, oxime bonds, imine bonds, imidebonds, and any combination thereof.
 61. The method of claim 1, whereinthe reaction of the chemical reaction site and a reactant, or thereaction of different reactants, results in the formation of at leastone bond selected from the group consisting of —NHN(R)CO—; —NHB(R)CO—;—NHC(RR′)CO—; —NHC(═CHR)CO—; —NHC₆H₄CO—; —NHCH₂CHRCO—; —NHCHRCH₂CO—;—COCH₂—; —COS—; —CONR—; —COO—; —CSNH—; —CH₂ NH—; —CH₂CH₂—; —CH₂S—;—CH₂SO—; —CH₂SO₂—; —CH(CH₃)S—; —CH═CH—; —NHCO—; —NHCONH—; —CONHO—;—C(═CH₂)CH₂—; —PO₂ ⁻—NH—; —PO₂ ⁻CH₂—; —PO₂ ⁻CH₂N⁺; —SO₂NH⁻—; andlactams.
 62. The method of claim 1, wherein complementary reactivegroups of the chemical reaction site and/or the reactive group(s) of oneor more reactants reacting with each other and/or with the chemicalreaction site are selected from the group consisting of a) activatedcarboxyl groups, reactive sulfonyl groups and reactive phosphonylgroups, or a combination thereof, and complementary primary or secondaryamino groups; wherein the complementary reactive groups react undersuitable conditions to form amide, sulfonamide and/or phosphonamidatebonds; b) epoxide groups and complementary primary and/or secondaryamino groups; wherein a reactant comprising one or more epoxide reactivegroup(s) reacts with one or more amine-group(s) of a complementaryreactant under suitable conditions to form one or more carbon-nitrogenbond(s); c) aziridine groups and complementary primary or secondaryamino groups; wherein under suitable conditions, a reactant comprisingone or more aziridine-group(s) reacts with one or more amine-group(s) ofa complementary reactant to form one or more carbon-nitrogen bond(s); d)isocyanate groups and complementary primary or secondary amino groups,wherein a reactant comprising one or more isocyanate-group(s) reactswith one or more amino-group(s) of a complementary reactant undersuitable conditions to form one or more carbon-nitrogen bond(s); e)isocyanate groups and complementary hydroxyl groups; wherein a reactantcomprising one or more isocyanate-group(s) reacts with a complementaryreactant comprising one or more hydroxyl-groups under suitableconditions to form one or more carbon-oxygen bond(s); i) amino groupsand complementary carbonyl groups; wherein a reactant comprising one ormore amino groups reacts with a complementary reactant comprising one ormore carbonyl-group(s); wherein the amines react with such groups viareductive amination to form a carbon-nitrogen bond; g) phosphorous ylidegroups and complementary aldehyde and/or ketone groups; wherein areactant comprising a phosphorus-ylide-group reacts with an aldehydeand/or a ketone-group of a complementary reactant under suitableconditions to form eg. a carbon-carbon double bond; h) complementaryreactive groups reacting via cycloaddition to form a cyclic structure;such as the reaction of alkynes and organic azides, which react undersuitable conditions to form a triazole ring structure; i) alkyl halidegroups and one or more nucleophile group(s), such as amino groups,hydroxyl groups and carboxyl group; wherein such groups react undersuitable conditions to form a carbon-nitrogen bond (alkyl halide plusamine) or carbon oxygen bond (alkyl halide plus hydroxyl or carboxylgroup); and j) halogenated heteroaromatic groups and one or morenucleophile group(s), wherein the reactants react under suitableconditions via aromatic nucleophilic substitution; wherein halogenatedheteroaromatic groups are optionally selected from chlorinatedpyrimidines, triazines and purines, which react with nucleophiles, undermild conditions in aqueous solution. 63-88. (canceled)
 89. The method ofclaim 1, wherein the chemical reaction site comprises a scaffoldcomprising one or more reactive groups.
 90. The method of claim 89,wherein the scaffold reactive groups are selected from the groupconsisting of carboxylic acids, alcohols, thiols, aldehydes, ketones,amides, imides, amines, azo, diazo, azido, hydrazines, carbamates,esters, thioesters, cyanides, ethers, isocyanates, isothiocyanates,sulfides, nitriles, nitrites, nitrates, nitro, peroxides, phosphates,thiophosphates, sulfides, epoxides, anhydrides, halides, acid halides,organometallics, nitrides, phosphides, carbides, and silicides.
 91. Themethod of claim 89, wherein scaffold comprises a scaffold moietyselected from the group consisting of quinazoline, tricyclicquinazoline, purine, pyrimidine, phenylamine-pyrimidine, phthalazine,benzylidene malononitrile, amino acid, tertiary amine, peptide, lactam,sultam, lactone, pyrrole, pyrrolidine, pyrrolinone, oxazole, isoxazole,oxazoline, isoxazoline, oxazolinone, isoxazolinone, thiazole,thiozolidinone, hydantoin, pyrazole, pyrazoline, pyrazolone, imidazole,imidazolidine, imidazolone, triazole, thiadiazole, oxadiazole, furan,benzoffuran, isobenzofuran, dihydrobenzofuran, dihydroisobenzofuran,indole, indoline, benzoxazole, oxindole, indolizine, benzimidazole,benzimidazolone, pyridine, piperidine, piperidinone, pyrimidinone,piperazine, piperazinone, diketopiperazine, metathiazanone, morpholine,thiomorpholine, phenol, dihydropyran, quinoline, isoquinoline,quinolinone, isoquinolinone, quinolone, quinazolinone, quinoxalinone,benzopiperazinone, benzodiazepine, quinazolinedione, benzazepine,azepine, tropane, and coumarine.
 92. The method of claim 1, wherein themolecule is a branched or cyclical molecule.
 93. The method of claim 92,wherein the molecule is cyclical and comprises a ring system selectedfrom a single ring system and a fused ring system.
 94. The method ofclaim 93, wherein one or more heteroatoms are present in either thesingle ring system or in the fused ring system.
 95. The method of claim93, wherein the single ring system is not directly bonded at more thanone ring atom to another closed ring, and wherein the fused ring systemis directly bonded at more than one ring atom to another closed ring.96-111. (canceled)
 112. The method of claim 1, wherein the molecule issynthesised by one or more reactions selected from the group consistingof amine acylation, reductive alkylation, aromatic reduction, aromaticacylation, aromatic cyclization, aryl-aryl coupling, [3+2]cycloaddition,Mitsunobu reaction, nucleophilic aromatic substitution, sulfonylation,aromatic halide displacement, Michael addition, Wittig reaction,Knoevenagel condensation, reductive amination, Heck reaction, Stillereaction, Suzuki reaction, Aldol condensation, Claisen condensation,amino acid coupling, amide bond formation, acetal formation, Diels-Alderreaction, [2+2]cycloaddition, enamine formation, esterification, FriedelCrafts reaction, glycosylation, Grignard reaction, Horner-Emmonsreaction, hydrolysis, imine formation, metathesis reaction, nucleophilicsubstitution, oxidation, Pictet-Spengler reaction, Sonogashira reaction,thiazolidine formation, thiourea formation and urea formation.
 113. Themethod of claim 1, wherein the one or more chemical reaction site(s) arecovalently linked to the one or more priming site(s). 114-115.(canceled)
 116. A method for the synthesis of a plurality of differentbifunctional complexes, said method comprising the steps of i) providinga plurality of display oligonucleotides each attached to a) one or morechemical reaction site(s) comprising one or more reactive groups and b)one or more priming site(s) for enzymatic addition of a tag, ii)providing a plurality of first reactants each comprising one or morechemical entities and one or more reactive groups, each first reactantbeing capable of reacting with c) the one or more chemical reactionsite(s) of the display oligonucleotide, and/or d) one or more reactivegroups of a first further reactant comprising one or more chemicalentities, wherein said first further reactant is provided simultaneouslyor sequentially in any order with the first reactant, iii) providing aplurality of first oligonucleotide tags each capable of hybridising topart of a first oligonucleotide anti-tag, wherein each firstoligonucleotide tag identifies a first reactant and, optionally, afurther first reactant, iv) providing a plurality of firstoligonucleotide anti-tags each capable of hybridising to at least partof a first oligonucleotide tag provided in step iii) and to at leastpart of a display oligonucleotide provided in step i), v) reacting eachof the first reactants provided in step ii) with c) the one or morechemical reaction site(s) of the display oligonucleotides and/or with d)the one or more reactive groups of a first further reactant comprisingone or more chemical entities, wherein the reaction of complementaryreactive groups result in the formation of a covalent bond, and whereinone or more reactive group reactions of step v) result in the formationof one or more covalent bond(s) between the one or more chemicalreaction site(s) of the display oligonucleotides and at least onechemical entity of at least one reactant selected from the groupconsisting of a first reactant and a further first reactant, vi)hybridising anti-tags to display oligonucleotides and to firstoligonucleotide tags, wherein method steps v) and vi) are simultaneousor sequential in any order, vii) enzymatically ligating displayoligonucleotides and first oligonucleotide tags, viii) dividing theplurality of nascent bifunctional complexes obtained in step vii) into aplurality of different compartments, ix) providing in each differentcompartment a plurality of different second reactants each comprisingone or more chemical entities and one or more reactive groups capable ofreacting with c) the one or more chemical reaction site(s) of each ofthe display oligonucleotides, and/or d) one or more reactive groups ofone or more reactant(s) having reacted in a previous synthesis round,and/or e) one or more reactive groups of a second further reactantcomprising one or more chemical entities, wherein said second furtherreactants are provided simultaneously or sequentially in any order withthe second reactants, x) providing in each different compartment aplurality of second oligonucleotide tags each capable of hybridising topart of a second oligonucleotide anti-tag, wherein different secondoligonucleotide tags are provided in each different compartment, andwherein each different second oligonucleotide identifies a differentsecond reactant and, optionally, a further second reactant which may bethe same or a different further second reactant in each differentcompartment, xi) providing in each different compartment a plurality ofsecond oligonucleotide anti-tags capable of hybridising to part of afirst oligonucleotide tag provided in step iii) and to part of a secondoligonucleotide tag provided in step x), xii) reacting in each differentcompartment each of the different second reactants provided in step ix)with c) the one or more chemical reaction site(s) of a displayoligonucleotide and/or d) one or more reactive groups of one or morereactant(s) having reacted in a previous synthesis round and/or e) oneor more reactive groups of a further second reactant comprising one ormore chemical entities, wherein said one or more reactions result in theformation of different bifunctional complexes in each differentcompartment, wherein the reaction of complementary reactive groupsresult in the formation of a covalent bond, and wherein one or morereactive group reactions of step xii) result in f) the formation of oneor more covalent bond(s) between the one or more chemical reactionsite(s) and at least one chemical entity of at least one reactantselected from the group consisting of second reactants and furthersecond reactants, and/or g) the formation of one or more covalentbond(s) between a reactant having reacted in a previous synthesis roundand at least one chemical entity of at least one reactant selected fromthe group consisting of second reactants and further second reactants,xiii) hybridising anti-tags to first oligonucleotide tags and secondoligonucleotide tags in each different compartment, wherein method stepsxii) and xiii) are simultaneous or sequential in any order, xiv)enzymatically ligating in each different compartment first and secondoligonucleotide tags in the absence of ligation first and secondanti-tag oligonucleotides, and optionally xv) displacing in eachcompartment unligated anti-tags from bifunctional complexes comprising amolecule and a single stranded oligonucleotide identifier comprisingtags identifying the reactants which participated in the synthesis ofthe molecule.
 117. The method of claim 116 comprising the further stepof mixing bifunctional complexes from each different reactioncompartment.
 118. The method of claim 117, wherein, in any roundsubsequent to the first round, the end product of the preceding round ofreaction is used as the nascent bifunctional complex for obtaining alibrary of different bifunctional complexes.
 119. The method of claim116, wherein steps viii) to xiv) are repeated once or more than onceusing different reactants and tags identifying said different reactants.120-123. (canceled)
 124. A method for identifying a molecule, saidmethod comprising the steps of subjecting the library produced by themethod of claim 116 to assaying conditions resulting in the partitioningof some, but not all molecules, from the remainder of the library, andidentifying the molecule(s) by decoding the identifier oligonucleotideof the bifunctional complex.
 125. The method of claim 124, wherein thelibrary is contacted with a target and wherein bifunctional complexeshaving an affinity for the target are partitioned form the remainder ofthe library. 126-129. (canceled)
 130. The method of claim 125, whereinthe identifier oligonucleotide of the one or more partitionedbifunctional complexes, optionally attached to a molecule, and furtheroptionally provided with one or more chemical reaction sites, issubjected to a method for synthesizing a plurality of molecules, saidmethod comprising the steps of: (a) forming a first group of subsets ofidentifier oligonucleotides comprising a plurality of nucleic acid tags,where the identifier oligonucleotides in each subset each has a selectedone of a plurality of different first hybridization sequences, a mixtureof different second hybridization sequences, and one or more chemicalreaction site(s), (b) reacting the chemical reaction sites in each ofthe subsets formed in (a) with a selected reagent, thereby forming areagent-specific molecule intermediate on the associated sequence ineach subset, (c) forming a second group of subsets of the reactedidentifier oligonucleotides comprising a plurality of nucleic acid tags,where the identifier oligonucleotides in each subset each have aselected one of a plurality of different second hybridization sequences,and a mixture of different first hybridization sequences; and (d)reacting the molecule intermediates in the sequences in each of thesubsets formed in (c) with a selected reagent.
 131. The method of claim130, wherein each of said forming steps includes hybridizing theidentifier oligonucleotides comprising a plurality of nucleic acid tagswithin a given subset with a plurality of solid phase reagents eachhaving a surface bound oligonucleotide or oligonucleotide analog capableof forming base-specific duplexes with one of the hybridizing sequencesin the given subset to bind each nucleic acid tag to one of thereagents.
 132. (canceled)
 133. The method of claim 130, for use informing a plurality of small molecules with different chemicalsequences, wherein each of said reacting steps includes adding aselected chemical substituent to each of the subsets of identifieroligonucleotides comprising a plurality of nucleic acid tags underconditions effective to add that substituent to the chemical reactionsite or last-added substituent carried thereon. 134-139. (canceled) 140.A bifunctional complex comprising a molecule and a single strandedidentifier oligonucleotide identifying the molecule, wherein the singlestranded identifier comprises a plurality of covalently linked tagswhich are at least partly hybridised to one or more correspondinganti-tag(s), wherein the anti-tags are not covalently linked to eachother. 141-160. (canceled)
 161. A library of different bifunctionalcomplexes according to claim 140.